Modulation of Synaptic Processes in Cortical Neurons in
Response to Painful Stimulation and Analgesia
Tamaz
Sh Labakhua, Tinatin K Janashia, Gulnara I Gedevanishvili
Tamaz
Sh Labakhua, Tinatin K Janashia, Gulnara I Gedevanishvili, LEPL Ivane Beritashvili Center of Experimental
Biomedicine, Tbilisi, Georgia
Correspondence to: Tamaz Sh Labakhua, LEPL Ivane
Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia.
Email: labakhuat@mail.ru
Telephone: +995-32-2375796
Received: December 19,
2014
Revised: February 8, 2015
Accepted: February 9, 2015
Published online: May 13, 2015
ABSTRACT
We
studied effects of electrical stimulation of the substantia nigra (SN), locus
coeruleus (LC), raphe nuclei (RN), substantia innominata (SIn), nucleus
caudatus (NC) and central grey (CG) on postsynaptic processes evoked in neurons
of the cat somatosensory cortex by excitation of nociceptive and
non-nociceptive afferent inputs (intense stimulation of the dental pulp and
moderate stimulation of the thalamic ventroposteromedial nucleus, VPMN,
respectively). We analyzed intracellularly recorded activity of cortical cells
activated exclusively by stimulation of nociceptors and cells activated by both
nociceptive and non-nociceptive influences (nociceptive and convergent
neurons). In neurons of both groups, stimulation of both nociceptive afferents
and thalamic VPMN resulted in the development of successions of EPSP C action
potential (AP) or their series C IPSP (IPSP duration 200C300 msec).
Conditioning electrical stimulation of the above-mentioned nuclei induced
suppression of synaptic reactions that occur in cortical neurons in response to
stimulation of nociceptive inputs. The maximum decrease in the amplitude of the
IPSP was observed at test intervals of 600 to 800 msec when stimulated nuclei
containing biogenic amines and 100-150 msec at conditioning electrical
stimulation of cholinergic structures. We observed certain parallelism between
conditioning influent ions of CG activation and effects of systemic injections
of morphine. Discusses is the physiological significance of presumebly
dendritic action potentials observed in our experiments. Decrease in the
amplitude or complete postsynaptic inhibition of IPSP in cortical neurons under
different treatments associate with the occurrence of convulsive epileptic
activity, and at the painful action with analgesic effect. Discussed are the
mechanisms for modulatory influences exerted by conditioning stimulation of SN,
LC, RN, NC, SIn and CG on the somatosensory neurons, activated upon excitation
of high-threshold (nociceptive) afferent inputs. Such modulation is probably
based on changes developing in both pre and post-synaptic intracortical
mechanisms.
© 2015 ACT. All
rights reserved.
Key words: Somatosensory cortex; Synaptic transmission;
Nociception; Modulation of postsynaptic reactions; Analgesia
Labakhua TS,
Janashia TK, Gedevanishvili GI. Modulation of Synaptic Processes
in Cortical Neurons in Response to Painful Stimulation and Analgesia. International Journal of Neurology Research 2015; 1(2): 51-67 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/983
INTRODUCTION
The problems of extracellular and intracellular signaling and its
participation in control of the living systems are recognized to be one of the
major directions in modern fundamental sciences, which are also used in
clinical medicine for treatment and correction of the certain CNS disorders.
Etiology of a
number of psychic and neurological diseases (schizophrenia, mood disorders,
anxiety disorders and oth.) is underlined by description of functioning in
dysfunction of various ekstrathalamic stem-cortical neurochemical systems. One
of the most up-to-date methods to study the role played by different neurotransmitter
systems in the regulatory mechanisms of cortical processes is to address the
synaptic processes in the cerebral cortex.
The process of
synaptic transmission, including the potential-evoked action of a
neurotransmitter release from the presynaptic terminals and a subsequent stage
of generating the postsynaptic potential, may be regulated or modulated at the
pre- and postsynaptic level. Activation of presynaptic receptors by their own
neurotransmitter (presynaptic auto regulation) provides maintenance of its
concentration in the synaptic clefts within definite limits, i.e. creates
conditions for an optimal functioning of the synapse. Receptors of other
mediators too may be localized at the presynaptic terminals. The membrane of
presynaptic terminal of central neurons is not a homogeneous structure, but
contains a variety of receptors through which the neurotransmitters, as well as
hormones regulate the synaptic transmission (presynaptic heteroregulation or
presynaptic modulation). Another group of factors that has stirred up interest
in studying the means and mechanisms governing synaptic transmission and which
had not found their reflection in classical comprehension of a synapse had been
the data on postsynaptic modulation of the effects of transmitters. In a number
of cases the interaction of two postsynaptic potentials, evoked by activation
of different synaptic inputs does not lead to the summation based on passive
properties of the neuronal membrane, but is mediated by special intracellular
second messenger of cyclic amino-mono-phosphate (cAMP) and cyclic guanosin
monophospate (cGMP) type.
The main
synaptic inputs to a definite population of neurons in the somatosensory cortex
are formed by ascending pathways of the system of nociception. Some neurons of
this neocortical population are strictly selectively activated by nociceptive
influences, while other cells of the mentioned population are excited upon
stimulation of both high-threshold (nociceptive) and low-threshold
(non-nociceptive) somatic afferents. Such neuronal groupings form a higher
floor of the nociceptive sensory system and, according to the conventional
classification, can be considered a cortical section of the nociceptive
analyzer. Information on the morphological, electrophysiological, and
neurochemical characteristics of such cortical neurons remains relatively
limited[1,2].
Noradrenergic
and dopaminergic (NA- and DA-ergic, respectively) cerebral systems are
important brainstem complexes exerting modulatory actions on the activities of
practically all parts of the brain cortex. The locus coeruleus (LC) is a
central structure in the NA-ergic brain system, while the substantia nigra (SN)
occupies the corresponding position in the DA-ergic system. The modulatory effects
of activation of neuronal systems of the LC and SN on neuronal activity in
different functional subdivisions of the cortex have attracted considerable
interest from experimenters[3-6]. In this case, however, studies of
the effects exerted by the LC and SN on neurons of the somatosensory cortex
were mostly directed toward reactions evoked in cortical neurons by activation
of relatively low-threshold afferents. At the same time, information on NA- and
DA-ergic modulation of the cortical activity related to nociceptive synaptic
influences is relatively limited. The question on the pattern of convergence of
the effects of these systems on nociceptive neocortical neurons remains open.
In addition, the amount of experimental material obtained in our earlier studies
was relatively limited. This was explained, to a great extent, by the necessity
to provide rather long-lasting recording from single cortical neurons; this
circumstance resulted in the exclusion from the analyzed material of a
significant proportion of the records that were insufficiently qualitative.
Recently, the
leading role of serotonergic (5--ergic) neurons localized in the dorsomedial
structures of the gray matter of the brain in the induction of central
analgesia[7] and the involvement of the raphe nuclei (RN)
containing such neurons in the phenomena of analgesia and hyperalgesia of an
opioid nature[8] were demonstrated. At the same time, some aspects
of the involvement of cortical neurons in the mechanisms of pain and analgesia
remain little studied. The activity of cortical neurons belonging to the
nociceptive system, similarly to the activity of neurons of other cerebral
structures, underwent considerable modulatory influences coming from a number
of the cerebral centers. The serotonergic (5-HT-ergic) brainstem system is one
of the most important systems exerting modulatory actions on the activity of
cortical neurons[7-10]. Nerve cells of the RN form rather
significant monosynaptic projections to the cortex[11,12]. It is
believed that they are capable of providing considerable modulation of the
functioning of cortical neurons. The earlier obtained data on the RN-born
effects on the activity of neurons of the somatosensory cortex concerned mostly
reactions of these cells evoked by excitation of relatively low threshold
afferents. Unfortunately, up to present there are only fragmentary data on
modulation of the activity of cortical neurons initiated by incoming of
nociceptive influences via high-threshold afferent inputs. Studies devoted to
elucidation of physiological characteristics and topography of cortical neurons
involved in the process of nociception, as well as of cellular and membrane
mechanisms underlying functioning of the above units, are relatively scant[13,14].
The cholinergic
cerebral system affects the activity of practically all structures of the
cerebral cortex. Results of histochemical and immunocytochemical studies
demonstrated that fibers of the cholinergic system in the cortex are formed by
two sources, intracortical bipolar radially oriented neurons localized in
cortical layers II-IV and corticopetal fibers coming from the basal forebrain
nuclei and Brokas diagonal ligamentum[11]. As is believed,
ascending axons of neurons of the basal ganglia (nucleus caudatus (NC), globus
pallidus, putamen, and substantia innominata (SIn) are the main source of
acetylcholine (ACh) in the somatosensory cortex. In carnivores, the nucl.
basalis magnocellularis, an analogue of the nucleus of Meynert in primates,
contains cells localized in the ventral and medial parts of the globus pallidus
and substantia innominata (SIn), and these neurons are cholinergic units[15,16].
Results of the neurophysiological and behavioral experiments and clinical
observations showed that the basal ganglia are involved in the processing of
both pain-related and non nociception-related information. Most neurons of the
basal ganglia are activated mostly by nociceptive stimulation and probably can
encode the intensity of a pain stimulus; they are involved in sensory
discrimination of the painformation, and translation of the corresponding
information to motor cortical areas[16,17]. At present, the effects
of the basal nuclei on the activity of neurons of different functional cortical
subdivisions are attracting considerable interest among researchers[17-21].
As is shown,
electrical stimulation of the cerebral central (periaqueductal) grey (CG)
significantly modifies nociceptive stimulation-induced responses in neurons of
the spinal cord and brainstem[22] and also in thalamic neurons[23].
Such stimulation noticeably influences the field electrical activity of mostly
neocortical genesis, evoked potentials (EPs). At the same time, the effects of G
stimulation on synaptic processes in single neurons of the cerebral cortex,
which, according to the characteristics of their synaptic inputs, belong to the
system of nociception, remain little studied.
Introduction
of micro doses of opiate alkaloids and opioid peptides in the CNS induces
clearly expressed analgesic effects[24]. Such experimental
observations demonstrate that the G is specifically related to the
antinociceptive cerebral system whose functions are realized with involvement
of opioid receptors. The distribution of such receptors in subcortical brain
structures has been studied in detail, but information on the effects of
opioidergic cerebral systems on various neuronal populations of the cerebral
cortex still remains fragmentary[2].
Taking into
account the above situation, we continued our examination of the above-listed
aspects and tested modulatory effects exerted by stimulation of the SN, LC, RN,
NC, SIn and CG on postsynaptic
reactions in neurons of the cat somatosensory cortex receiving excitatory
synaptic influences from nociceptive afferents[25-29].
METHODS
Acute experiments were carried out on; the experimental technique was
in accordance with requirements of the International Association for Studies of
Pain. Surgical procedures (tracheotomy, cannulation of the femoral vein,
pneumothorax, and trepanation of the skull above the pericruciate cortical
area) were performed under ether inhalation anesthesia, and then the animals
were injected with 40 mg/kg -chloralose. According to the stereotaxic
coordinates[30], bipolar Constantan wire electrodes with standard
insulation (interpolar distance 0.5 mm) were inserted into the regions
corresponding to the LC, SN, RN, NC, SIn, CG and thalamic VPMN. Electrodes were
fixed to the skull bones by a fast-hardening plastic. The accuracy of introduction
of the stimulating electrode in the thalamic VPMN was additionally controlled
by stimulation of this nucleus and mapping of the maximum activity focus (MAF)
within the somatosensory cortex; evoked potentials (EPs) were recorded using a
ball microelectrode.
Drillings were
made in the upper fangs by a dental burr, and thin wire electrodes insulated
except for their tips touching the dental pulp were introduced and fixed in the
openings using dental cement. The animal was immobilized by i.v. injection of a
myorelaxant (d-tubocurarine or arduane) and artificially ventilated. The edges
of the surgical wounds and fixator pressing regions were thoroughly
anesthetized with Novocain. Before immobilization, we tested effects of
stimulation of the dental pulp and measured the pain threshold (PT) according
to initiation of the mouth opening reflex.
The activity
of cortical neurons was intracellularly recorded using standard techniques.
Glass microelectrodes filled with 2.0 potassium citrate were inserted into
the somatosensory cortical zone under visual control. Neurons were identified
as cells of the first group (nociceptive units) in the case when synaptic
potentials were evoked in them exclusively by stimulation of afferents of the
dental pulp with the superttreshold (2.0 threshold, or more) intensity. Weaker
stimulations did not evoke any postsynaptic responses in such neurons. Neurons
of the second group (convergent units) were excited by stimulation of both the
dental pulp, as well as by stimulation of the thalamic VPMN with 3 to 5 T
intensity.
After the
experiment, electrical current providing electro coagulation labeling of the
stimulated sites in the LC, SN, RN, NC, SIn and CG was passed through the
respective stimulating electrodes. Localization of the tips of the latter was
histologically verified on frontal brain slices. Numerical data were treated
statistically using standard techniques, in particular Students t-test.
Intergroup differences were considered to be significant in the cases with P0.05.
I. Responses of
nociceptive neurons of the neocortical somatosensory zone and glial cell to
stimulation of the tooth pulp
Intracellular recordings of satisfactory quality (membrane potential,
MP, not less than 58-60 mV throughout the entire recording period) were
obtained in our study from neurons localized within the primary somatosensory
cortical area. The depth of recording of most of the above neurons varied from
1.5 to 2.8 mm. Some cells were identified, according to the above-described
criteria, as nociceptive neurons (responding exclusively to strong stimulation
of the dental pulp exciting and afferent fibers), while others were
convergent, possessing synaptic inputs from both pain and non-nociceptive
afferents. In most nociceptive neurons, relatively weak (about 1.5 to 2.0 T
with respect to initiation of the reflex of mouth opening in a non-immobilized
animal) stimulation evoked small-amplitude EPSPs (Figure 1A, 1). An increase in
the strength of a single stimulus resulted in an increase in the EPSP amplitude
and arrival of a longer-latency hyperpolarization potential; the latter was
probably also a postsynaptic event, i.e., an IPSP (Figure 1A, 2, 3).
Upon further
intensification of stimulation, EPSP exceeded the threshold for generation of
the action potential (AP), and the response to single stimulation of the dental
pulp acquired a complex EPSP-AP-IPSP pattern (Figure 1A, 4).
In some nociceptive neurons
characterized by a relatively low frequency of the background activity, suprathreshold
stimulation of the dental pulp of both ipsi- and contralateral fangs evoked
several APs arriving on the EPSP maximum, and this was followed by strong
hyperpolarization (IPSP) (B). In neurons generating high-frequency background
spiking, responses to stimulation of the dental pulp (EPSP-AP-IPSP complexes)
were evoked with comparatively short latencies (C). The development of IPSP
after synaptically evoked APs resulted in inhibition of background impulsation;
the duration of such suppression periods can reach 100-200 msec (in the neuron
whose activity is shown in figure 1D, such a period was about 170 msec long).
There was no response of glial cells to painful stimulation (Figure1D, 2-3).
Intergroup differences were considered to be significant in the cases with P0.05
II. Modulation
of postsynaptic responses of nociceptor-activated neurons of the cat
somatosensory cortex by stimulation of the substantia nigra
In this study, we examined the effects of conditioning electrical
stimulation of the SN on postsynaptic responses of neurons of the somatosensory
cortex. Responses of the neurons to high-threshold (nociceptive) stimulation of
the dental pulp was used as the test reaction (Figure 2, A and C); in
convergent neurons, stimulation of the thalamic VPMN activating corticopetal
pathways of both nociceptive and non-nociceptive neurons was also used (Figure
3, A and C). Intracellular recordings preserving satisfactory quality
throughout a rather long period (the membrane potential, MP, did not drop below
C58 mV within these periods) were obtained from 17 neurons localized within the
borders of the primary somatosensory cortex; (such a rather strict criterion of
the selection mode compelled us to ignore a significant part of the recorded
units). The depth of localization of most the above neurons varied from 1.5 to
2.8 mm. Among the analyzed units, 7 cells were identified according to the
above-described criteria as nociceptive (they responded exclusively to strong
stimulation of the dental pulp, i.e., activation of the receptors connected
only with and fibers). Ten neurons were qualified as convergent units
activated by both nociceptive (pain) and relatively low-threshold afferents.
Intracellularly recorded responses of nociceptive cortical neurons to
stimulation of the dental pulp appeared as a complex EPSP-action potential
(AP)-IPSP (Figure 2A, 1; C,1). Responses of convergent cortical neurons to
stimulation of the thalamic VPMN also included EPSP with one AP (Figure 3 C,
2-8) or a burst of APs generated with a high intraburst frequency (Figure 3 A,
2-7). After these excitatory components, postsynaptic hyperpolarization (IPSP)
developed; it lasted about 200 to 250 msec, and its amplitude reached, under
our conditions of recording, 6 to 10 mV. This complex response was probably
generated due to summation of the effects of nociceptive and non-nociceptive
influences .For activation of the SN, we used short high-frequency (200-250
sec-1) series of stimuli. Isolated stimulation of the SN by such high-frequency
series evoked two types of responses in the examined cortical neurons. In a
part of the convergent neurons (4 of cells out of 10), stimulation of the SN
evoked long-lasting (several hundreds of milliseconds) EPSPs. These potentials
were characterized by a complex time course, and APs were generated on their
maxima. The frequency of these spikes exceeded the frequency of background
spiking of these neurons. We cannot rule out that such impulses were dendritic
APs (Figure 3A, 2-7).
In all
nociceptive and remaining convergent neurons, hyperpolarizing IPSPs of a rather
high amplitude (up to 8-10 mV) lasting 60 to 120 msec were primary reactions to
stimulation of the SN. In the course of these potentials, generation of
background impulse activity was blocked (Figure 2 A, recordings 2-7, 2C,
recordings 2-8, and 3A, recordings 2-7). In the case where stimulation of the
SN preceded test stimulation of the dental pulp or of the thalamic VPMN,
postsynaptic inhibitory components in the responses to test stimulation (in
complexes EPSP-AP-IPSP) were subjected to intense suppression at certain
conditioning/test intervals. The latencies of such inhibitory effects were
rather long and varied considerably from neuron to neuron. In some cells, this
inhibition began at test intervals about 100 to 200 msec (Figure 2B). In other
cortical neurons, the delay of such suppression can reach 200-300 msec (Figures
3B and 3D). In all cases, however, the maximum suppressive effect of
conditioning stimulation of the SN was observed at durations of the test
intervals about 350-700 msec (Figures 2B, 3B, 2D, and 3D). The total duration
of the inhibitory effect reached at least several seconds (not illustrated). A
relatively limited number of observations make difficult accurate statistical
treatment, but we should note a somewhat greater intensity of suppression of
IPSPs in cortical nociceptive neurons under the influence of conditioning
stimulation of the SN, as compared with the corresponding effects in convergent
neurons (this fact can be illustrated by a comparison of figure 2 with figure
3). Initial excitatory postsynaptic components in complex responses of cortical
neurons to stimulations of the dental pulp, infraorbital nerve, or thalamic
VPMN could also be somewhat inhibited after conditioning stimulation of the SN,
but the intensity of inhibition of these components was rather moderate. Such
effects can be detected only under conditions of weakening of test stimulation.
We did not, however, examine these effects in detail. At least, they were much
less intense than suppression of post activating IPSPs. Intergroup differences
were considered to be significant in the cases with P 0.05
III. Modulation
of postsynaptic responses of nociceptor- activated neurons of the cat
somatosensory cortex by stimulation of the locus coeruleus
Isolated stimulations of the LC by short high-frequency series of
pulses induced two types of responses in the studied cortical neurons. We
selected 22 neurons localized within the primary somatosensory cortex. Among
them ten neurons were identified as nociceptive, while 12 neurons were
qualified as convergent units. In some nociceptive and convergent neurons,
stimulation of the LC by short bursts of stimuli resulted in the development of
long-lasting (several hundreds of milliseconds) complex EPSPs. Action
potentials were generated on the maxima of depolarization waves, and the AP
frequency exceeded the frequency of background activity (Figures 4 A, 2-8, and
5A, 2-8).
In another
part of nociceptive and convergent neurons, rather high-amplitude (up to 8-12
mV) hyperpolarization was the primary response to stimulation of the LC; these
IPSPs were 60 to 120 msec long. In the course of the development of such
hyperpolarization potentials, generation of the background activity was blocked
(Figures 4C, 3-8; 4C, 2-7).
In the case
where stimulation of the LC preceded test stimulation of the dental pulp or of
the thalamic VPMN, postsynaptic inhibitory components in the responses to test
stimulation (in complexes EPSP-AP-IPSP) were subjected to intense suppression
at certain conditioning/test intervals (Figures 4-5, panels B,D). Intergroup
differences were considered to be significant in the cases with P0.05.
IV. Raphe
stimulation-evoked modulation of postsynaptic responses by neurons of the cat
somatosensory cortex activated by stimulation of nociceptors
Fifteen cells that responded to stimulation of the dental pulp and
thalamic VPMN and corresponded to the above criteria of the analysis were
selected from all the studied cortical neurons, whose activity was recorded
intracellularly. The resting membrane potential (MP) of all these neurons
throughout the entire recording period was C58 mV or higher. Among them, six
cells were identified as selectively nociceptive, while nine units were
classified as convergent. The depth of localization of most of the above
neurons from the surface of the cortex varied from 1.23 to 2.50 mm.
Short-lasting high-frequency series of stimuli were found to be an effective
mode of RN stimulation. Such stimulation induced noticeable changes in the
background synaptic and impulse activity of the examined cortical neurons. In
some studied neurons, isolated stimulation of the RN caused discrete relatively
short-latency responses in the form of complex EPSPs (Figure 6 A); against the
background of such postsynaptic depolarization, one or several APs were
generated. In other cells where IPSPs of a significant amplitude and duration
(120 to 140 msec) appeared with nearly the same latency, generation of impulse
activity was blocked (Figure 6 A and C, 2-8).
However,
conditioning stimuli applied to the RN caused, independently of the type of the
initial response, long-lasting (several seconds) suppression of synaptic
responses induced in cortical neurons by stimulation of nociceptive inputs.
Intracellular reactions of nociceptive neurons responding to stimulation of the
dental pulp and also to intense stimulations of the thalamic VPMN (which
resulted in excitation of both nociceptive and nonnociceptive afferent
pathways) corresponded to the EPSPCAPCIPSP sequence (Figure 6). In the case
where conditioning stimulation of the RN preceded test stimulation of the
dental pulp or thalamic VPMN, all synaptic components of the responses to test
stimulation (EPSPCAPCIPSP) underwent intense suppression at certain intervals
between conditioning and test stimulations. Test intervals that provided a
maximum suppressing effect of conditioning stimulation of the RN were about 400
to 800 msec. It should be noted that the studied neurons of the somatosensory
cortex also generated impulses of a noticeably (in some cases, significantly)
smaller amplitude and duration in a parallel manner with full-sized (probably
somatic) APs. Such impulses could be observed both within the background
activity of nociceptive and convergent neurons of the studied cortical zone and
in the responses induced by stimulation of nociceptive afferents of the dental
pulp and thalamic VPMN. Such APs appeared more frequently after generation of
full-sized APs with relatively short intervals (no more than 10 to 15 msec,
usually 3 to 5 msec). In Figure 1 A and C, such APs are indicated by arrows.
However, impulses of a reduced amplitude and duration could, in some cases,
appear independently of full-sized APs or precede such APs. In Figure. 1A and
C, such situations are marked by arrows with letters (isolated). The
amplitudes of these APs demonstrated a high variability; the minimal values of
the amplitudes of these peaks were observed in the case where such APs appeared
after full-sized APs with the shortest intervals (Figure 6. A, C). Figure 7
shows intracellular activity from three cortical pyramidal neurons (Figure 7 A,
D, E). Passage of depolarizing current through the recording microelectrode
caused, alongside with somatic action potentials (AP), generation of dendritic
APs of different amplitude (Figure 7A). Recording of activity at varying circular
sweeps (Figure 7 B, C) testifies that the amplitude of the assumed dendritic
APs significantly differed from the amplitude of APs of the initial segment of
axon.
Figure 7 D
presents intracellular activity of another pyramidal neuron with simultaneous
recording of somatic and assumed dendritic APs. Upon artificial
hyperpolarization of a neuron disappeared only baseline somatic APs, whereas
the assumed dendritic ones maintained steady amplitude. On figure 7E baseline
activity (upper left) was presented only by somatic APs. When thalamic
VPMN was stimulated with 10/sec
frequency, alongside with APs, appeared evoked dendritic APs of different
amplitude and high-frequency on the background of pronounced EPSPs, arising
after delivery of each stimulus. Intergroup differences were considered to be
significant in the cases with P 0.05.
V Effects of
stimulation of the substantia innominata and caudate nucleus on
postsynaptic reactions of neurons of the cat somatosensory cortex activated by
excitation of nociceptors
We examined the effects of conditioning electrical stimulation of the
NC (Figure 8. A and B) and SIn (Figure 9.A and B) on postsynaptic reactions in
neurons of the somatosensory cortex. Short high-frequency (200-250 secC1)
series of stimuli were used for such stimulation.
Responses of
the neurons to stimulation of the tooth pulp (in the case of nociceptive
neurons) and of the pulp and thalamic VPMN, i.e., the effects of stimulation of
both nociceptive and non-nociceptive corticopetal pathways (in convergent
neurons), were used as test synaptic reactions. From the entire group of
intracellularly recorded cortical cells, we selected 16 neurons localized
within the primary somatosensory cortex; in these units, the membrane potential
(MP) exceeding C58 mV was preserved during the entire long-lasting period of
recording and testing. The depth of recording from the majority of such neurons
varied from 1.4 to 2.7 mm. Among the examined cells selected according to the
above-described criteria, seven neurons were identified as nociceptive, while
nine neurons were qualified as convergent units. In the case of sufficiently
high-quality intracellular recording, responses of nociceptive cortical neurons
to pain-inducing stimulation of the dental pulp included EPSPs accompanied by
single action potentials (APs) or bursts of several APs. This complex was
followed by a hyperpolarizing MP inclination (IPSP) (Figs. 8 A and 9A). The
IPSP amplitude in these cases could reach 6C8 mV, while the duration of these
inhibitory potentials was 250C300 msec. In all nococeptive and convergent
neurons, EPSPs were evoked primarily after isolated stimulations of the NC and
SIn.
In all
nococeptive and convergent neurons, EPSPs were evoked primarily after isolated
stimulations of the NC and SIn. These excitatory synaptic effects provided
generation of APs, and such complexes were followed by hyperpolarization PSPs
(IPSPs). The amplitude of the latter was rather significant (8-10 mV), and
their duration was 250-300 msec (Figures8 and 9). Thus, synaptic effects on
isolated stimulations of the NC and SIn were, in general, rather similar to
those evoked by nociceptive stimulation of the tooth pulp. In the cases where
stimulations of the NC and SIn preceded testing stimulation of the tooth pulp
or that of the thalamic VPMN, synaptic components of the responses to test
stimulation were intensely suppressed at definite intervals between conditioning
and testing stimulations. If the duration of interstimulation intervals was
equal to 100 to 200 msec, spike responses to test stimulations were completely
suppressed in nearly all cases (Figures 8 and 9). With increases in the
intervals between conditioning and testing stimulations, the amplitude of test
EPSPs gradually increased and reached a critical level for AP generation but
was still significantly lower than that in the control (P<0.05).
Thus, the test reaction partially recovered. The recovery was full or nearly
full (P>0.05) when the test reaction coincided with late phases of
after- IPSPs in response to conditioning NC or SIn stimulation or at longer
intervals (300-600 msec). Intergroup differences were considered to be
significant in the cases with P0.05.
VI Modulation
of postsynaptic responses of nociceptor-activated neurons of the cat
somatosensory cortex by stimulation of the Central Grey
Twenty one cells that responded to stimulation of the dental pulp and
thalamic VPMN and corresponded to the above criteria of the analysis were
selected from all the studied cortical neurons, whose activity was recorded
intracellularly. The resting membrane potential (MP) of all these neurons
throughout the entire recording period was C58 mV or higher. Among them, nine
cells were identified as selectively nociceptive, while twelve units were
classified as convergent. Single stimulation of the ipsilateral CG locus
evoked, as a rule, responses of nociceptive cortical neurons rather similar to
those evoked by dental pulp stimulation; they also looked like EPSP-AP-IPSP
complexes. The responses to CG stimulation, nonetheless, differed by shorter
latencies (Figure 10. A, 1, 2). It should be specially mentioned that a long
period of inhibition of background impulse activity (at least several hundreds
of milliseconds) was observed in these neurons after stimulation of the CG. If
a test stimulation of the dental pulp was applied within this period,
postsynaptic responses to such stimulation could be entirely suppressed;
neither EPSPs (and, moreover, trans-synaptically initiated APs) nor IPSPs were
evoked (Figure 10. A, 3). Figure 2B illustrates the effect of conditioning
stimulation of the CG on the response evoked by test stimulation of the
thalamic VPMN in one of the convergent neurons. In this case, short
high-frequency (200seC1) series containing three to eight stimuli were used.
This neuron was classified as a convergent unit because it generated
postsynaptic responses not only to stimulation of the dental pulp but also to
relatively low-intense stimulations of the infraorbital nerve and thalamic
VPMN. As can be seen in panel B, 1, strong stimulation of the thalamic VPMN
(probably activating both nociceptive and non-nociceptive pathways) evoked
EPSP-AP-IPSP complexes in this neuron. The inhibitory postsynaptic reaction was
followed by augmentation of spiking of this neuron (probably, a rebound
effect). Burst stimulation of the CG resulted in the development of a complex
synaptic response, containing both excitatory and inhibitory components. In the
case where stimulation of the CG was used for conditioning and the effect of
such stimulation was tested by stimulation of the thalamic VPMN, synaptic
potentials evoked by such testing were significantly suppressed at definite
interstimulation intervals. Afterspike IPSPs were suppressed especially
intensely. Such inhibition was characterized by a rather long latency (at least
100 msec) and reached its maximum at test intervals about 600-800 msec. Under
such conditions, the amplitude of these inhibitory potentials decreased by 50
to 70% (B).
Inhibitory
effects evoked by stimulations of the CG in nociceptive and convergent
somatosensory cortex neurons showed certain similarity to the effects of
systemic injections of 0.3 mg/kg morphine. In nociceptive neurons, the
amplitude of IPSP components in the EPSP-AP-IPSP complexes evoked by
stimulation of the dental pulp (i.e., by nociceptive stimulation) demonstrated
a severalfold drop as early as 1 min after i.v. injection of this agent (Figure
10 D, 1, 2). Simultaneously, a clear decrease in the frequency of background
activity generated by this neuron was observed. Three minutes after injection
of morphine, synaptic effects induced by dental pulp stimulation were completely
reduced (D, 3). This suppression was not related to depolarization of the
membrane of this neuron because the latter continued to generate background
spikes (although low-frequency). The amplitude of APs constituting this
background activity remained practically identical to that observed in the
initial state (D, 1). Five minutes after injection of morphine, synaptic
responses evoked by stimulation of the dental pulp remained completely
suppressed. Within this period, background impulse activity in nociceptive
neurons was usually absent, and only low-amplitude synaptic noise was
noticeable. It should be emphasized that the MP showed no considerable changes
within this period, as compared with the initial state (D, 4). Changes in the
background activity and synaptic responses induced in convergent neurons by
systemic introduction of morphine were rather specific. An example of such
modulation is shown in Fig.10 E. This neuron generated comparatively
high-frequency background activity and responded to stimulation of the thalamic
VPMN by an EPSP-AP-IPSP complex. Injection of morphine resulted in a
progressive decrease in the amplitude of IPSP in the above reaction; on the 5th
min after injection, such depression of IPSP was more than twofold. Injection
of morphine, however, did not block generation of background synaptic activity
and background APs in this neuron (E, 2, 3). Intergroup differences were
considered to be significant in the cases with P 0.05.
DISCUSSION
Intracellular records obtained in our study from neurons of the
somatosensory cortex under conditions of the arrival of afferent volleys via
ascending nociceptive pathways demonstrate that synaptic responses evoked in
cortical neurons after corticopetal bursts of a specific pain modality are, in
general, rather similar to responses of somatosensory cortex neurons to the
influences of other sensory modalities. The magnitude of such nociceptive
responses depends in a gradual manner on the intensity of stimulation of
nociceptors of the dental pulp.
Results of our
study show that responses of nociceptive and convergent neurons of the
sensorimotor cortex to sufficiently strong stimulation of the main afferent
inputs, when recorded intracellularly, appear as EPSP-AP-IPSP complexes.
Conditioning stimulation of the SN preceding test stimulation with certain
(rather long) intervals induced intense selective suppression of late
inhibitory postsynaptic components in these complex responses.
Isolated
stimulation of the SN by short high-frequency pulse series could result in
generation of two types of responses in the studied cortical neurons. In a
noticeable part of convergent neurons, long-lasting (several hundreds of
milliseconds) synaptic excitation with a complex polycomponent time course was observed
after burst stimulation of the SN. The development of such EPSPs could result
in generation of APs with a frequency exceeding the frequency of background
activity. If we take into account the pattern of these APs, they can supposedly
be considered dendritic spikes. At the same time, hyperpolarization (IPSPs) of
rather high amplitude was the primary reaction to SN stimulation in all
nociceptive neurons and the remaining part of the convergent units.
Two components
should probably be differentiated in the effects induced by stimulation of the
SN. These are immediate synaptic effects on the target cells and DA-ergic
modulation of synaptic transmission provided by other neurotransmitters. In
monkeys (Macaque), DA-containing corticopetal afferents coming from the SN form
symmetric contacts on the somata and dendrites of pyramidal cells in the
prefrontal, cingular, and motor cortices. Such innervation provides direct
modulating effects of DA released from terminals of nigrofugal fibers on the
excitability of cortical neurons[31]. Intracellular recording from
neurons in frontal slices of the anterior regions of the rat neocortex showed
that DA exerts an excitatory effect on pyramidal cells and GABA-ergic neurons
sending axons that terminate on pyramidal cells[5]. At the same
time, in slices of the guinea-pig hippocampus, applications of both DA and its
agonist apomorphine evoked hyperpolarization mediated by changes in the Ca2+
activated potassium permeability of the membrane[32]. In the SN
neurons themselves, DA also induced hyperpolarization; it decreased the input
resistance due to an increase in the potassium permeability[33]. The
DA-ergic cerebral system in neurons of the rat striatum is capable of exerting
significant modulatory influences on the activity of cholinergic interneurons
and effects of neurotransmitter amino acids[34,35]. As was reported
earlier, cholinergic responses in synapses formed by neurons in the rat retina
are subjected to DA-ergic modulation[36]. Such modulation of
cholinergic responses in the medial prefrontal cortex of rats is mediated by D1
and D2 receptors[37]. Mutual modulatory effects of such monoamines
as DA and serotonin, when they act on neurons of the spinal ganglia of rats, is
related to changes in the intracellular activity of secondary messengers[38].
Iontophoretic application of DA to neurons of the striatum modified the
capability of glutamate of activating postsynaptic neurons; this finding is one
more proof of the neuromodulatory role of DA[39].
The published
data indicate that there are two systems responsible for generation and
suppression of IPSPs; these systems function at the thalamic and cortical
levels. Cortical IPSPs elicited by thalamic stimulation are of an intracortical
nature, and their suppression is also realized at the cortical level.
Suppression of
cortical IPSPs can reflect the development of inhibitory postsynaptic processes
in the intracortical inhibitory interneuronal system, i.e., postsynaptic
inhibition of inhibition. In this case, however, manifestations of switching
on of the disinhibition mechanism should be observed practically from the very
beginning of action of conditioning volleys. At the same time, the powerful
effect of conditioning stimulation of the SN was observed in our experiments at
significant delays of test stimulation with respect to the conditioning one; it
reached its maximum at intervals of 300 to 700 msec. In the context of our
experiments, we prefer to interpret suppression of postactivating IPSPs in
neurons of the somatosensory cortex as manifestation of generalized modulatory
suppression of synaptic inputs evoked by activation of nociceptive inputs and
not as a phenomenon of purely synaptic inhibition of inhibition.
As was
mentioned above, the effects of the DA system, whose fibers monosynaptically
project to the cerebral cortex, can evoke increases in the levels of cAMP and
cGMP and also of calcium ions in the nerve cells. These effects are realized
via the corresponding receptors. Activation of the latter results in activation
of protein kinases, phosphorylation of membrane proteins, and an increase in
the responsiveness of neurons in many cerebral regions.
A decrease in
the amplitude of IPSPs in nociceptive neurons upon the conditioning influence
of stimulation of the SN can be related to the action of DA on the system of
secondary messengers. Analysis of two types of DA-initiated reactions in
neurons of the spinal ganglia showed that depolarization responses are related
to activation of D1 receptors and mediated by an increase in the conductivity
of cAMP-dependent sodium channels. At the same time, hyperpolarization
responses are initiated by activation of D2 receptors; this effect increases
the conductivity of potassium channels[38]. Application of DA and
intracellular injection of cAMP evoked the appearance of an inward current
related to an increase in the permeability for sodium ions[40].
According to other data, DA reversibly decreases in a dose-dependent manner the
amplitude and duration of afterhyperpolarization in pyramidal cells of the rat
hippocampus related to an increase in the Ca-dependent potassium conductance[41].
In convergent neurons, where IPSPs are generated due to the integral inflow of
pain and non-pain afferent volleys, stimulation of the SN suppresses effects of
only (or preferably) nociceptive afferent signals; this results in smaller
drops in the IPSP amplitudes. Such suppression of IPSPs in cortical neurons
induced by stimulation of the dental pulp and thalamic VPMN was also observed
at activation of the noradrenergic (NA-ergic) cerebral system[25].
Dopamine is reserved mostly in axonal vesicles of DA-ergic neurons. This
monoamine is a metabolic precursor of NA and is released in the course of
synaptic activation together with the above neurotransmitter[42].
Dopamine can regulate the sensitivity of the NA-ergic system, in particular via
influencing the state of -adrenoreceptors, e.g., in the prefrontal cortex of
rats[43].
Studies of the
mechanisms underlying development of postsynaptic effects of neuromodulators on
systems of intracellular messengers and on functions of receptor-linked ion
channels led to the conclusion that the effects of neurotransmitters undergo
divergence on receptors of different subtypes and, vice versa, the effects of
different neurotransmitters can converge on the same ion channels because the
systems of secondary messengers are to a great extent common[44].
Therefore,
comparison of our findings and the data published earlier allows us to conclude
that stimulation of the SN initiating DA-ergic influences on nociceptive
synaptic effects in neurons of the cat somatosensory cortex (via acting on DA
receptors of these neurons and the system of secondary messengers) provides
intense modulation of the activity of the respective populations of cortical
neurons. These effects should probably be interpreted as one of the aspects of
analgesic influences resulting from activation of the SN.
Effects of
stimulation of the LC and iontophoretic applications of its transmitter
(noradrenaline) in neurons of different cortical regions can be either
excitatory or inhibitory[45,46]. The excitability of neocortical
neurons can be noticeably modified under the influence of NA because of
suppression of slow potassium currents[47]. According to
observations on cerebral cortex slices[48], NA and DA exert
inhibitory influences on 2+ entries and glutamate release in
synaptic connections. On the other hand, there are indications that the
influences of NA and DA induce increases in the cAMP, cGMP, and 2+
levels in the nerve cells. This results in activation of protein kinases and
phosphorylation of membrane proteins; finally, this increases the
responsiveness of the neurons in many brain regions.
Stimulation of the
LC resulting in activation of adrenoreceptors on the membranes of target
cells, an increase in the activity of adenylate cyclase, and intensification of
cAMP production provides intensification of GABA-ergic inhibition. This was
shown on Purkinje cerebellar cells; similar processes can, probably, be
realized in cells of other cerebral systems[45]. Dopamine-containing
afferents coming from the SN form symmetric contacts on the somata and
dendrites of pyramidal cells of the prefrontal, cingular, and motor cortices in
macaques; such connections provide direct modulatory effects of DA on the
excitability of cortical projection neurons[6]. Intracellular
recording of neuronal activity in frontal slices of anterior regions of the rat
neocortex showed that DA exerts excitatory effects on pyramidal cells and
GABA-ergic neurons projecting to the above units[5]. It was also
demonstrated that DA-ergic neurons are involved in the control of sensitivity
of adrenoreceptors in the prefrontal cortex of rats[49]. In slices
of the hippocampus of guinea pigs, application of DA, similarly to that of its
agonist apomorphine, evoked hyperpolarization mediated by Ca2+ activated
potassium conductivity of the membrane[50,51]. It was shown that the
DA-ergic system modulates the activity of cholinergic neurons and efficacy of
action of neuromodulatory amino acids in neurons of the rat striatum[35].
Dopaminergic modulation of cholinergic responses in neurons of the rat
prefrontal cortex is mediated by D1 and D2 receptors[37].
Iontophoretic application of DA to striatal neurons modifies the ability of
glutamic acid to postsynaptically activate neurons; this fact confirms the significant
neuromodulatory role of DA[39].
In convergent
cortical neurons, where postactivation IPSPs represent an integral effect of
the arrival of both pain and non-nociceptive afferent influences, stimulations
of the LC and SN result in relatively selective suppression of pain afferent
signals; this also results in decreases in the IPSP amplitudes, but such
suppression is less intense than that in nociceptive neurons.
There is proof
that NA and met-enkephalins increase the potassium conductivity in CNS neurons
of the guinea pig; these effects are mediated by opioid receptors and 2
adrenoreceptors conjugated with potassium channels by GI proteins[52].
Nociceptive
stimulation was shown to increase NA release from the terminals of NA-ergic
neurons[53]. Electrical and chemical stimulation of the LC induces
antinociceptive effects realized at the spinal level[54]. Our
findings also demonstrate that stimulation of the LC and SN results in
long-lasting suppression of synaptic responses evoked in somatosensory cortex
neurons by stimulation of nociceptive afferents and ascending pathways.
Probably, such effects should also be interpreted as one of the aspects of
analgesic influences related to activation of the LC and SN, i.e., main
structures of cerebral NA- and DA-ergic systems.
As is known,
terminals of the axons of neurons of the LC, which exclusively and extensively
project to many structures of the brain, form not only classic synaptic
connections with target neurons but also a number of free NA-ergic terminal
structures (varicosities). Noradrenaline is released from these structures in
the intracellular space and, in such a way, can exert its influence
simultaneously on great populations of the neurons (providing the so-called
volume transmission)[55]. The temporal characteristics of LC
stimulation-induced suppression of synaptic effects (in particular, of
postactivation IPSPs) in somatosensory cortex neurons (long latencies and very
long duration of such modulatory effects) probably correspond just to such a
mode of the NA effects. In this case, modulatory influences of NA on the
efficacy of synaptic transmission from thalamic corticopetal afferents plays a
more significant role; at the same time, the importance of direct synaptic
action of NA-ergic inputs formed by LC neurons on cortical neurons, as well as
of NA-ergic modulation of the efficacy of functioning of intracortical
neuron-to-neuron systems, should not be underestimated.
Our results
agree with modern concepts on the nature of regulation of the pain sensitivity
at the level of higher CNS structures and allow us to conclude that the
modulatory effects induced by stimulation of the LC and SN with respect to
nociception-related processes in the somatosensory cortex demonstrate a significant
similarity to each other.
Our own
experiments and studies of other authors[27,56] showed that not only
the neurons selectively activated from ascending nociceptive pathways but also
the cells receiving both influences of a nociceptive character and influences
from lower threshold pathways (convergent neurons) are present in the
somatosensory cortex. The effects observed in such neurons after stimulation of
the RN using short high-frequency series of stimuli demonstrated certain
similarity to the responses caused by stimulation of the catecholaminergic
brainstem systems[27]. These responses could be easily divided into
two groups. Relatively short-latency discrete EPSPs or IPSPs of rather great
durations were one type of the observed effects. Since the number of our
observations is relatively small, we have no way of relating the type of
synaptic effects induced by stimulation of the RN to concrete functional
peculiarities of one cortical neuron or another. It should only be noted that
the number of cases of excitatory or inhibitory synaptic effect from the RN was
comparable in the examined group. The development of late very long nonspecific
suppression of all synaptic responses induced in such neurons by excitation of
somatic afferent pathways (both nociceptive and low-threshold) was another kind
of influences elicited by stimulation of the RN on the studied nociceptive and
convergent neurons of the cat somatosensory cortex. Such inhibition was rather
clearly pronounced with respect to IPSPs developing after the EPSP-AP complex.
The duration of such inhibitory effects exceeded 700 or 800 msec. At these test
intervals, we observed only the maximum of inhibition. Thus, the total duration
of the latter can exceed 1,500 msec.
Interpretation
of the mechanisms underlying postsynaptic effects induced by stimulation of the
RN in nociceptive and convergent neurons of the somatosensory cortex and, in
particular, those underlying long-lasting inhibitory modulation of synaptic
responses of such neurons, which results from the activation of somatosensory
inputs, is complicated. To a significant extent, it is determined by the fact
that membrane receptors sensitive to 5- (5- receptors) are rather diverse
and form a great number of subtypes and subgroups. The action of 5-, the main
neurotransmitter released by neurons of the RN, includes a rise in the cAMP
level, which is mediated by adenylate cyclase; in turn, cAMP activates
cAMP-dependent protein kinase, which results in phosphorylation of a great number
of substrate proteins, including proteins of potassium channels[57,58].
Therefore, it is obvious that an increase in the potassium conductance through
the membranes of nerve cells possessing 5- receptors is a basic effect
determined by the action of 5- and mediated by cAMP. This conclusion was
confirmed by the data obtained in experiments on different objects (neurons of
invertebrates and vertebrates)[38,59,60,61]. It is obvious that the
increase in the conductance through just calcium-activated potassium channels
dependent on 5-1 receptors but not through voltage-directed ones plays the
main role[38]. These effects are related to changes in the
intracellular 2+ concentration, which was demonstrated on
hippocampal neurons[62,63]. However, the action of 5- is,
probably, more complicated; as is hypothesized, this neurotransmitter/modulator
influences at least two different types of receptors; one of them provide
opening of potassium channels, while others mediate a decrease in the potassium
conductance[64].
The above
phenomena did not limit the complexity of the effects induced by the release of
5- into the tissues of different cerebral structures, including the
neocortex. Changes in the level of 5- exert a significant modulatory effect
on cholinergic transmission, which was found in different objects[65-68]
interaction of these agents is realized via both membrane receptors and systems
of intracellular signaling. This monoamine actively influences the neuronal
systems of GABA-ergic inhibition due, probably, to its direct action on
GABA-ergic inhibitory interneurons (in any case, in the hippocampus)[69].
The 5--ergic afferent inputs actively interact with neuronal chains where
glutamatergic transmission is realized[60,70,71]. The data on global
effect of 5- in the cortex are to a certain extent contradictory. It was
demonstrated that application of 5- facilitates early and late impulse
reactions of neurons of the somatosensory cortex, which are induced by tactile
stimulation, and modulates responses of many cells to conditioning stimulation[15].
On the other hand, it was found that excitatory responses of neurons of the rat
prefrontal cortex (evoked by pain stimulation of the tail or stimulation of the
thalamic mediodorsal nuclei) were significantly inhibited after preliminary
stimulation of the RN[72]. Our own observations agree with the data
obtained in the cited study and indicate that not only excitatory effects
observed in nociceptive and convergent cortical neurons but also postexcitatoryinhibition
in these cells undergo long-lasting (in any case, 1 sec long) depression after
stimulation of the RN using short high-frequency series of stimuli. The
nonspecific pattern of such depression and pattern of its time course
(significant latency and long duration) allows us to hypothesize that this
phenomenon is, to the great extent, of a presynaptic nature. The presence of
certain groups of 5- receptors on presynaptic terminals in the cortex has
been convincingly evidenced; it should be taken into account that presynaptic
5- autoreceptors provide autoregulatsion of the effects of the latter by the
feedback mechanism[73]. Therefore, stimulation of the RN results in
the release of 5- and increase in the 5-HT level in the cortex. Serotonin
influences target neurons via numerous and diverse 5- receptors and the
system of secondary messengers and, in such a way, provides considerable
modulation of the activity of the corresponding populations of cortical
neurons. The most important effect is, in this case, general nonselective
suppression of synaptic reactions of cortical neurons evoked by activation of
nociceptive inputs
During the
last years, certain success was achieved in the understanding of the mechanisms
of pain perception and formation. At the same time, a number of insufficiently
examined theoretical and practical aspects remained. At present, a number of
channels transmitting modulatory influences on the cerebral cortex have been
identified. These are pathways coming from the raphe nuclei, locus coeruleus,
and nonspecific, associative, and relay thalamic nuclei. In addition, there is
another extrathalamic channel transmitting nonspecific effects on the cortex;
it originates from the basal forebrain structures. These structures (NC, globus
pallidus, putamen, and SIn) contain large cholinergic neurons and send
topically organized projections to the cortex. Activation of caudate cortical
mono- and oligosynaptic pathways evokes relatively short-latency responses in
the cortex. The caudate nucleus, acting both directly and via nonspecific
nuclei of the thalami optici and midbrain reticular formation, polysynaptically
affects the activity of the brain cortex; these effects significantly modulate
the parameters of this activity[74]. Glutamate is released from
presynaptic terminals in various regions of the brain after any nociceptive
impact. As is believed, realization of physiological pain-related reactions
(e.g., a defensive reflex of the limb withdrawal) upon the action of glutamate
is mediated via AMPA receptors; NMDA receptors provide in this case
long-lasting hyperactivity of nociceptive neurons (under certain conditions,
this activity is pathological)[75]. The activating effects of
glutamate on nociceptive neurons are potentiated by substance P. This agent
coexists as a modulator in more than 90% glutamate-containing terminals of
high-threshold sensory fibers. Substance P, when interacting with NK1
(neurokinin-1) receptors not only increases the concentration of intracellular
calcium by its mobilization from intracellular stores, but also intensifies the
activity of NMDA receptors. At present, nitric oxide (NO), which plays the role
of a no typical extrasynaptic mediator, is considered an important factor in
the mechanisms providing sensitization of nociceptive neurons. Nitric oxide is
produced from L-arginine in neurons containing NO-synthase. It is released from
cells upon NMDA induced excitation and interacts with presynaptic terminals of
C afferents (intensifies glutamate and neurokinin release from these
structures)[76]. Pathological hyperalgesia is based on sensitization
of nociceptors with respect to the action of injuring stimuli.
Electrophysiologically, sensitization of nociceptors is manifested as decreases
in the threshold of their activation and enhancement of the frequency and
duration of discharges in nervous fibers of groups A and C; these events
result in increase in the intensity of the afferent nociceptive drive.
According to the concept of Kryzhanovskii[77], aggregates of
interacting sensitized neurons with abnormally modified inhibitory mechanisms
and increased excitability are the structural bases of neurogenic pain
syndromes. Such aggregates can produce long-lasting self-maintained
pathological activity; initiation of the latter does not necessarily require
input of afferent impulsation from the periphery. An important role in the
mechanisms of formation of neuronal hyperactivity in the CNS structures is
attributed to suppression of glycine and GABA-mediated inhibitory responses.
Under conditions of functional insufficiency of inhibitory mechanisms and
increased excitability of neurons, neuron-to-neuron activating synaptic
interactions are facilitated, the activity of silent inactive synapses is
triggered, and neighboring sensitized neurons are united in an integral
aggregate. Sensitization of nociceptive neurons can be related to injury of
tissues resulting in increases in the excitability and responsiveness of
nociceptive neurons in the abovementioned centers (including thalamic nuclei
and somatic cortex of the hemispheres).
Acetylcholine
exerts diverse postsynaptic actions on neurons of the CNS. Different types of
responses to application of ACh are manifested in various CNS structures to
different extents. Even within a single CNS structure, the effects of ACh of
neurons of different types can be dissimilar. Depolarizing ACh-induced
potentials in neurons of invertebrates (mollusks) are related to increased
permeabilitys of the membrane to ions of Na+, Ca2+, and
small amounts of ClC. Activation of nicotinic receptors induces
mostly sodium permeability, while that of muscarinic receptors intensifies
calcium permeability[78]. The effects of ACh result in modulation of
glutamatergic transmission. The depolarizing effect of glutamate on the
membrane of motoneurons of the isolated frog spinal cord resulted from
increases in the permeability to Na and K cations[79]. The action of
glutamate and aspartate on large nerve cells of the rat cerebellum evoked inward
sodium currents[80]. Glutamatergic influences induced increase in
the content of Ca in neurons of cerebral cortex[81]. The involvement
of ACh in the mechanisms of suppression of IPSPs in pyramidal neurons of
hippocampus was demonstrated. In this case, the effects are mostly mediated by
muscarinic receptors; in particular, they induce suppression of recurrent
inhibition. Acetylcholine also acts on a presynaptic level; it suppresses
either the activity of inhibitory interneurons or GABA release from presynaptic
terminals[82]. Acetylcholine can influence the activity of
hippocampal pyramidal cells via two pathways, postsynaptically (by modulation
of the permeability of the somatic membrane to cations) and presynaptically (by
modulating the efficacy of noncholinergic inputs)[83]. According to
some authors, the postsynaptic actions of Ach are manifested as slow muscarinic
depolarization elicited due to decrease in the voltage-dependent potassium
current, and, probably, intensification of sodium and calcium currents. The
presynaptic action of ACh is either realized through direct effects of
presynaptic terminals or mediated by interneurons. After examination of
neuronal activity in the somatosensory cortex before and after Ach
applications, it was concluded that the cholinergic system modulates sensory
processes in the cortex by changes in the efficacy of influences of afferent
inputs on neurons in all layers of the cortex[84]. Acetylcholine
induces fast excitation of neurons related to increase in the permeability to
cations and mediated by nicotinic and muscarinic receptors. In a parallel
manner it results in the development of slow excitation resulting from decrease
in the potassium permeability and blocks the Ca-dependent potassium
permeability[85]. In pyramidal cells of cortical layer V,
application of ACh evoked EPSP-IPSP complexes and suppressed slow
afterhyperpolarization following generation of APs. Cholinergic inhibition in
the cortex is mediated by fast excitation of nonpyramidal GABA-ergic cells[86].
Studies of changes in the permeability of the membrane of nerve cells within
different sections of after-potentials and postsynaptic hyperpolarization
potentials and involvement of ion channels in their genesis allowed researchers
to form a well based conclusion that such inhibitory potentials are
multicomponent. Their initial component is mostly determined by increase in the
membrane permeability to ClC ions and, in many cases, can be
identified as a synaptic GABAA-mediated response. The second component is mostly
determined by potassium current and should be interpreted as a synaptic
GABAB-mediated response. The terminal component is related mostly to
Ca-dependent potassium current. These components are manifested in nearly all
CNS neurons. They are not sharply separated in time, partially overlap with
each other, and form a long-lasting integral hyperpolarizing potential
deviation[87]. In our experiments, the most intense suppression of
impulse responses and inhibitory synaptic effects in sensorimotor cortex
neurons to test stimulation of the tooth pulp or thalamic VPMN was observed
within the initial period of development of IPSPs after conditioning
stimulations of the SIn and NC. Within this period, depolarizing potentials are
suppressed, and such inhibition is related to the action of inward chloride
current and a drop in the resistance of the postsynaptic membrane. Testing
stimulations of the tooth pulp or thalamic VPMN in the course of the second
IPSP component (i.e., within the period of functioning of GABAB-mediated
transmission) evoke generation of partially suppressed slow depolarization
whose amplitude was in some cases sufficient for generation of single or
several APs.
In other
words, partial recovery of the test response was noticed within this time
interval. Full or nearly full recovery of the responses to test stimulation of
the tooth pulp and thalamic VPMN corresponded to the final part of the
hyperpolarization potential and to cases where the intervals between
conditioning and test stimulations exceeded the duration of the
hyperpolarization potentials evoked by conditioning SIn and NC stimulations.
Therefore, stimulations of the NC and SIn result in ACh release in the cortex;
ACh acts upon target neurons via nicotinic and muscarinic receptors. This
provides strong modulation of activity of the corresponding populations of
nociceptive and nonnociceptive cortical neurons.
Our
observations agree with the results of earlier studies where the development of
clearly expressed analgesia was found under conditions of electrical
stimulation of the CG or microinjections of opiate alkaloids or opioid peptides
into this structure [88,89, 90]. It is known that neurons of the CG (at least,
a considerable part of them) are enkephalin and dinorphinergic units. About
half of these neurons are excited or inhibited upon nociceptive stimulation,
and these cells possess relatively clearly delineated receptive fields. As is
supposed, opioidergic neuronal systems play a crucial role in the processes
determining processing of nociceptive information at the higher CNS levels.
Opioids probably realize their modulatory function at a presynaptic level, via
inhibition of neurotransmitter release into synaptic connections of nociceptive
neuronal networks. It is believed that enkephalin-type endogenous opioids
suppress the entry of 2+ into presynaptic terminals, i.e., the
process necessary for exocytose of the neurotransmitter and its release into
the synaptic cleft. Such effects of endogenous opioids are imitated by the
action of their exogenous agonists, morphine-like alkaloids and their
derivatives[41]. The results of our experiments, where a certain
similarity between the effects evoked in cortical nociceptive and convergent
neurons by electrical stimulation of the CG and systemic introduction of
morphine was demonstrated, can be interpreted as proof of the existence of the
above mechanism. Both influences result in suppression of EPSPs and IPSPs,
i.e., in general depression of the synaptic effects evoked by activation of
nociceptors. These influences also induce decreases in synaptic potentials in
convergent neurons. We should note that, nonetheless, the effects of
stimulation of the CG and introduction of morphine manifest certain specificity
with respect to the above cells. Our experiments demonstrate that there is
certain parallelism between modulatory effects of stimulation of the CG, LC,
and SN exerted on nociceptive processes in the somatosensory cortex. As was
shown[91,92], activation of both the LC (the main source of NA-ergic
effect) and the SN (the source of DA-ergic projections) in many cases exert no
considerable effects on the evoked activity generated by neurons in various
cerebral centers. In other cases, the effects induced by stimulation of the
above structures are rather significant. In these effects of stimulation of the
LC and SN, two components should be differentiated. These are immediate
synaptic effects on target cells and modulation of synaptic effects exerted by
other neurotransmitters by LC- and SN-born influences. Actions of both types
exert considerably weaker influences on those synaptic processes in convergent
neurons, which are related to the arrival of impulsation via non-nociceptive
pathways.
A great number
of data indicating that spreading APs can be generated in dendrites of neurons
of different CNS structures of vertebrates has been accumulated at present.
Findings made in the course of presumably intradendritic microelectrode
recordings indicate that depolarization of the membrane of many central neurons
can, in principle, evoke, in some cases, APs in dendrites according to the
all-or-nothing mode and that these potentials can reach the soma of the cell
and can be recorded as APs distinguished by a reduced amplitude and duration.
Taking into account an increased variability of the amplitude of presumably
dendritic APs observed in our experiments, the possibility that such potentials
are initiated in the first axonal segment of the studied cortical neurons is
ruled out. Based on the parameters (amplitude and T) of the putative dendritic
APs recorded from one and the same neuron, we can hypothesize that multiple
trigger zones of generation of APs exist in neocortical cells[93,94].
According to the existing viewpoint, the putative dendritic APs are, to a
considerable extent, provided by currents through calcium channels, which can
be distributed along the membrane of both the soma and dendrites. In this
relation, the data on significant effects of some neurotransmitters and
neuropeptides on calcium currents attract specific interest. In particular, it
was demonstrated that 5- increases the concentration of intracellular 2+
[75,95]. Therefore, rather intense stimulation of the RN used in our
experiments could, to a certain extent, promote generation of dendritic APs.
The ability of neuronal dendrites to generate APs independently of the events
in the main trigger zone of the neuron (axon hillock) appreciably complicates
the ideas of integrative processes in nerve cells as the simple algebraic
summation of depolarizing and hyperpolarizing influences on the somatodendritic
membrane. In particular, summation of excitatory effects to the generation
threshold for APs can probably be realized not only in the axon hillock but
also in multiple loci of the dendrites. The dendrite apparatus is considered to
be a complex neurochemical integrator [94].
Different neurotransmitters act upon target neurons and this provides
strong modulation of activity of the corresponding populations of nociceptive and
nonnociceptive cortical neurons. Such modulation is probably based on changes
developing in both pre and post-synaptic intracortical mechanisms.
Development of
IPSP on the bodies of pyramidal cortical neurons is associated with activity of
system of intracortical recurrent inhibition. In the presynaptic and
postsynaptic inhibition are involving different transmitters. Postsynaptic
inhibition removed by a number of pharmacological agents (strychnine et al)
enhances presynaptic inhibition, whereas picrotoxin suppressing presynaptic
inhibition has no effect on postsynaptic inhibition.Decrease in the amplitude
or complete postsynaptic inhibition of IPSP in cortical neurons under different
treatments associate with the occurrence of convulsive epileptic activity, and
at the painful action with analgesic effect.
CONFLICT OF INTERESTS
The Authors have no conflicts of interest to declare.
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Peer reviewer: Guo-Gang Xing, MD.,
Ph.D., Professor of Neurobiology, Department of Neurobiology, School of Basic
Medical Sciences, Peking University Health Science Center, Neuroscience
Research Institute, Peking University, 38 Xue-Yuan Road, Beijing 100191, P.R.
China.
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