Limbic influence on the periaqueductal gray: A single unit study in the awake squirrel monkey

Single neurons of the periaqueductal gray (PAG) were studied during electrical stimulation of the amygdala and hippocampus. Fifty-one percent (34/67) of the units sampled throughout the rostrocaudal extent of the PAG were found to have a limbic influence. PAG neurons were characterized by low spontaneous firing rates (X¯= 4.94 spikes/sec). Units responded to basolateral amygdala stimulation primarily with short duration excitatory responses having a mean latency of 30 ms (range: 13.3–110 ms). Responses to corticomedial and lateral amygdala stimulation produced different patterns of activation including complex excitatory and inhibitory sequences. Only 10 units (15%) sampled in PAG responded to hippocampal stimulation with excitatory or tonic-inhibitory responses. The majority of responsive units (8) were to anterior hippocampal stimulation (latency range: = 20–75 ms). High frequency (9 Hz) basolateral amygdala stimulation recruited responses with increases in the probability of firing and a decrease in initial latency and latency variability.     

Periaqueductal gray inhibition of trigeminal subnucleus caudalis unitary responses evoked by dentine and nonnoxious facial stimulation

The possible pain inhibitory effects of periaqueductal gray (PAG) stimulation were investigated in cats anesthetized with Nembutal and immobilized with Flaxedil. Unitary responses evoked by electrical stimulation of the upper canine dentine and by cutaneous facial noxious and nonnoxious stimuli were recorded extracellularly from the trigeminal subnucleus caudalis. A bipolar electrode was introduced into the PAG to test the effects of PAG excitation on the trigeminal response to dentine (TRED) and cutaneous nonnoxious stimulation. In some experiments, a similar electrode was lowered into the contralateral posterior thalamus to study the antidromic activation of subnucleus caudalis cells and the effects of thalamic stimulation on the TRED. Dentine stimulation evoked brief (6- to 15-ms) bursts of 1 to 10 spikes with 3- to 25-ms latencies. Most units (88%) were also activated by cutaneous facial stimulation. Stimulation of the posterior thalamus had no effect on the TRED or on responses to cutaneous stimulation, but activated antidromically 10% of the units. In 71% of the units PAG stimulation inhibited the TRED. In some of those cases (12%), the inhibitory effect persisted 30- to 60 s. The PAG stimulation could produce paradoxical effects, potentiating the TRED evoked by threshold intensity and inhibiting the TRED elicited by suprathreshold stimulation. About one-half the PAG points evoked detectable effects. Their location had no clear topographical distribution, although ventral sites were more potent than dorsal sites. Responses evoked by nonnoxious facial stimulation were also inhibited by the PAG.     

The effects of periaqueductal gray and nucleus raphe magnus stimulation on the spontaneous and noxious-evoked activity of lateral reticular nucleus neurons in rabbits

In urethane-anesthetized rabbits the effects of periaqueductal gray (PAG) and nucleus raphe magnus (NRM) stimulation on the spontaneous and the noxious-evoked activity of the lateral reticular nucleus (LRN) neurons were studied. The PAG and the NRM stimulating electrodes were located in the optimal sites for suppressing the jaw-opening reflex (JOR) evoked by the tooth pulp stimulation. It was found that the 12% of neurons tested were affected by one or both stmuli. A total of 80 responsive neurons (52% antidromically activated by the cerebellum) were analyzed. Out of these neurons, 31 showed a convergence to both stimuli, 43 responded only to PAG and 6 only to NRM. Noxious heat stimulation of the contralateral foot was effective in altering the activity of 60% of these neurons. The PAG and NRM stimuli modified the noxious-evoked responses in most of these units. While the excitation was the predominant effect on the spontaneous activity (52 cells), the inhibition was predominant on the noxious-evoked activity (29 cells). These results indicate the presence of connections from PAG and NRM to LRN, probably devoted to the processing of the nociceptive information.     

Intracellular responses of raphe magnus neurons during the jaw-opening reflex evoked by tooth pulp stimulation

Neurons in the nucleus raphe magnus (RM) may play an important role in the modulation of nociception. To determine how RM neurons are activated during a nociceptive reflex, the intracellular responses of raphe neurons were studied during the jaw-opening reflex (JOR) elicited by tooth pulp shock in lightly anesthetized cats. Tooth pulp stimulation produces reflex EMG activation of the digastric muscle at a latency of 7-11 ms, resulting in jaw opening. Tooth pulp shock that elicits the JOR also produces an EPSP in a subset of raphe neurons. This EPSP consists of an early small depolarization that occurs at a latency of 10-15 ms followed by a larger depolarization at a latency of 20-60 ms. In all cases the latency to EPSP is longer than the latency to digastric EMG onset. Electrical stimulation of the 4 paws elicits oligosynaptic EPSPs in the same cells at a latency of 16-20 ms. Electrical train stimulation of the midbrain periaqueductal gray region (PAG) suppresses the JOR. Single shock stimulation at the same PAG sites that suppress the JOR evokes monosynaptic EPSPs in the large majority of raphe neurons recorded. In all cases, the threshold for EPSP is below the threshold for suppression of the JOR. The EPSP amplitude is a direct function of PAG stimulus intensity and there is temporal summation of EPSPs evoked by paired PAG shocks. At condition-test intervals of 40-90 ms, train stimulation of PAG suppresses the tooth pulp-evoked EPSP in raphe neurons. The threshold for EPSP suppression occurs at a PAG stimulation intensity below that required for suppression of the JOR. The present findings provide evidence that RM neurons may play an important role in the modulation of the tooth pulp-evoked JOR, but only after the initial withdrawal reflex has occurred.     

Chronic Spinal Nerve Ligation Induces Changes in Response Characteristics of Nociceptive Spinal Dorsal Horn Neurons and in Their Descending Regulation Originating in the Periaqueductal Gray in the Rat

We studied whether a chronic neuropathy induced by unilateral spinal nerve ligation changes the response characteristics of spinal dorsal horn wide-dynamic range (WDR) neurons or their periaqueductal gray (PAG)-induced descending modulation. Experiments were performed in rats with behaviorally demonstrated allodynia induced by spinal nerve ligation and in a group of nonneuropathic control rats. The stimulus–response functions of WDR neurons for mechanical and thermal stimuli and the modulation of their peripherally evoked responses by electrical stimulation of the PAG were determined under pentobarbital anesthesia. The results showed that neuropathy caused a significant leftward shift in stimulus–response functions for mechanical stimuli. In contrast, stimulus–response functions for noxious heat stimuli in the neuropathic limb were, if anything, shifted rightward, although this shift was short of statistical significance. In neuropathic rats, PAG stimulation produced a significantly stronger attenuation of spinal neuronal responses induced by noxious heat in the unoperated than in the operated side. At the intensity that produced attenuation of noxious heat stimuli, PAG stimulation did not produce any significant change in spinal neuronal responses evoked by mechanical stimuli either from the operated or the nonoperated hindlimb of the neuropathic rats. Spontaneous activity of WDR neurons was higher in the operated side of neuropathic rats than in control rats. Afterdischarges evoked by peripheral stimuli were observed in 1/16 of the WDR neurons ipsilateral to spinal nerve ligation and not at all in other experimental groups. The WDR neurons studied were not activated by innocuous or noxious cold stimuli. The results indicate that spinal nerve ligation induces increased spontaneous activity and enhanced responses to mechanical stimuli in the spinal dorsal horn WDR neurons, whereas noxious heat-evoked responses are not significantly changed or if anything, attenuated. Moreover, the inhibition of noxious heat stimuli by PAG stimulation is attenuated in the neuropathic side. It is proposed that the observed changes in the response characteristics of the spinal dorsal horn WDR neurons and in their descending modulation may contribute to the neuropathic symptoms in these animals.     

Effects of electrical stimulation of thalamic nucleus submedius and periaqueductal gray on the visceral nociceptive responses of spinal dorsal horn neurons in the rat

Electrical stimulation of the nucleus submedius (Sm) has been shown to suppress the viscerosomatic reflex (VSR), which is evoked by colorectal distension (CRD). We have examined the effects of focal electrical stimulation (0.3 ms, 50 Hz, 100 microA, 10 s) of the Sm and the periaqueductal gray (PAG) on the excitatory responses evoked by CRD in spinal dorsal horn neurons within the L6-S1 region in the urethane-anesthetized Wistar rats. Extracellular recordings were made from 32 spinal excitatory CRD responses. All of these neurons were convergent neurons with cutaneous receptive fields. The majority of the neurons (27/32) were wide dynamic range (WDR) neurons (responding to noxious and non-noxious cutaneous stimuli) while the remaining five neurons were nociceptive specific (NS) neurons (responding only to noxious cutaneous stimuli). The effects of electrical stimulation applied to 28 sites within the Sm were assessed for spinal neurons. Electrical stimulation in seven sites within the Sm (25%) inhibited the CRD excitatory response of dorsal horn neurons, while in two sites (7%) the same stimulation yielded facilitation. Electrical stimulation in the majority of the sites in the Sm (19/28, 68%) did not affect spinal excitatory CRD responses. On the other hand, electrical stimulation of the PAG clearly inhibited 20 of 22 (90%) CRD excitatory responses. These results suggest that the majority of Sm neurons may suppress VSR activity at a supraspinal reflex center rather than via a descending inhibition of spinal visceral nociceptive transmission, as is the case for the PAG.     

Suppression of the jaw-opening reflex by periaqueductal gray stimulation is decreased by paramedian brainstem lesions

Electrical stimulation of the midbrain periaqueductal gray region (PAG) suppresses the tooth pulp-evoked jaw-opening reflex (TP-JOR). In the present study the pathways that mediate this suppression were investigated by placing brainstem lesions in lightly anesthetized cats. Parasagittal lesions that interrupted the afferent and efferent connections of the medullary and pontine raphe nuclei attenuated (but did not abolish) suppression of the TP-JOR evoked by PAG stimulation. This result provides further evidence that medial brainstem structures partially mediate the effects of PAG stimulation in the trigeminal system.     

Inhibition of spinal cord interneurons by narcotic microinjection and focal electrical stimulation in the periaqueductal gray matter

Single cell evoked activity was recorded from spinal cord interneurons in rats prepared with microinjection cannulae or stimulating electrodes in the periaqueductal central gray matter (PAG). Morphine microinjections (4–16 μg) inhibited the response evoked by a noxious stimulus in 55% of the wide dynamic range neurons tested. Microinjections of etorphine (0.25–0.5 μg) inhibited 82% of the nociceptive neurons tested. Neither drug inhibited neurons which responded only to innocuous mechanical stimulation. The inhibition of wide dynamic range neurons produced by narcotic microinjection was antagonized by naxolone (1 mg/kg, i.p.) in 7 of 11 cases. Control experiments indicated that the effects obtained with microinjections could not be attributed to the drugs' diffusion to the spinal cord. Focal electrical stimulation of the PAG inhibited the responses to noxious stimuli of 60% of wide dynamic range neurons but was without effect on the responses of neurons that were activated only by innocuous stimuli. These experiments directly demonstrate that narcotic analgesics restricted to an intracerebral site of action activate a neural system which preferentially inhibits the responses of spinal cord wide dynamic range neurons to noxious stimuli. The system has a specificity for nociceptive input since non-nociceptive neurons were unaffected. Directly comparable results were produced by electrical stimulation of the PAG, supporting the concept that stimulation and narcotics modulate the transmission of nociceptive information by similar mechanisms.     

An ascending serotonergic pain modulation pathway from the dorsal raphe nucleus to the parafascicularis nucleus of the thalamus

(1) Three types of spontaneously active neurons were found in the parafascicularis (PF) nucleus of the thalamus of the rat: slow firing units (0.5–10 spikes/s), bursting units (2–5 spikes/burst in 10–20 ms, one burst every 1–2 s) and fast firing units (15–40 spikes/s). A similar population of neurons was found in the PF of rats treated with 5,7-dihydroxytryptamine (5,7-DHT), a serotonin neurotoxin.

(2) Noxious tail pinch (TP) caused 68% of the PF neurons to increase their firing rates to 242% of their initial baseline activity, while non-noxious touch stimulation failed to induce a response. In the 5,7-DHT-treated rats, TP caused 85% of the neurons in the PF to increase their firing rates to 581% of their initial baseline activity and 22% of the neurons increased their firing in response to touching the tail. Both the number of cells responding (P < 0.05) and the percentage increase (P < 0.001) were statistically greater in serotonin-depleted rats than in controls. This indicates that serotonin (5-HT) has a tonic inhibitory influence on responses to both noxious and non-noxious sensory stimuli.

(3) In control rats, electrical stimulation of the dorsal raphe nucleus (DR) decreased the firing rates of PF neurons. In contrast, the same DR stimulation induced an increase in PF firing rates during stimulation in serotonin-depleted rats and this increase in firing rates remained several seconds after cessation of stimulation. This indicates that the DR may use at least two different neurotransmitters in its projections to forebrain structures.

(4) In control rats, the TP stimulation induced an increase in firing rates of PF neurons while DR stimulation attenuated the excitation induced by TP stimulation. In serotonin-depleted rats, DR stimulation and TP both caused an increase in firing rates. This effect was not additive indicating that there may be a serotonergic projection from the DR to the PF which modifies responses to somatosensory stimuli.

(5) The inhibitory effects elicited by electrical stimulation were limited to the immediate area of the DR. Stimulation of the adjacent reticular formation 1 mm lateral to the DR produced the opposite effect, an increase in firing rate often accompanied by driven spike activity in the PF.

Effect of stimulation in the periaqueductal grey matter on activity in ascending axons of the rat spinal cord: selective inhibition of activity evoked by afferent Aδ and C fibre stimulation and failure of naloxone to reduce inhibition

In rats with prenigral decerebration, the effect was studied of electrical stimulation of the periaqueductal grey matter (PAG) on the activity recorded from axons ascending in the spinal cord. These axons were activated by electrical stimulation of afferent Aβ, Aδ and C fibres in the ipsilateral sural nerve.Stimulation of the PAG with trains of impulses by itself evoked ascending activity, but strongly depressed the impulse transmission from C fibres to neurones with ascending axons. It exerted a weaker effect on impulse transmission from Aδ fibres and had no effect on impulse transmission from Aβ fibres to neurones with ascending axons. Intravenous naloxone, 1 mg/kg, did not diminish the depressant effect of PAG stimulation.Intravenous morphine depressed the activation of ascending axons from afferent C fibres (0.5 mg/kg) more markedly than that from afferent Aδ fibres (2 mg/kg), but did not modify the depression of ascending activity produced by PAG stimulation. Naloxone antagonized the depressant effect of morphine.The results indicate that PAG stimulation inhibits ascending activity evoked by noxious stimuli by a mechanism which does not necessarily involve endogenous opiates.     

Common patterns of increased and decreased Fos expression in midbrain and pons evoked by noxious deep somatic and noxious visceral manipulations in the rat

Immunohistochemical detection of the protein product (Fos) of the c-fos immediate early gene was used to study neuronal activation in the rostral pons and midbrain of halothane-anesthetised rats following noxious deep somatic or noxious visceral stimulation. In animals exposed only to halothane anesthesia. Fos-like immunoreactive (IR) neurons were located in the midbrain periaqueductal gray matter, tectum, and parabrachial nucleus. Following noxious stimulation of hindlimb muscle, knee joint, vagal cardiopulmonary, or peritoneal nociceptors, there was, compared to halothane-only animals, a significant increase in the numbers of Fos-like (IR) cells in the caudal ventrolateral periaqueductal gray and the intermediate gray lamina of the superior colliculus. Given the general agreement that increased Fos expression is a consequence of increased neuronal activity, the finding that a range of noxious deep somatic and noxious visceral stimuli evoked increased neuronal activity in a discrete, caudal ventrolateral periaqueductal gray region is consistent with previous suggestions that this region is an integrator of deep noxious evoked reactions. The noxious deep somatic and noxious visceral manipulations also evoked, compared to halothane-only animals, reductions in the numbers of Fos-like IR cells in the stratum opticum of the superior colliculus and the unlaminated portion of the external subnucleus of the inferior colliculus. To our knowledge this is the first report of reductions in Fos-expression in the tectum evoked by noxious stimulation. In separate experiments, the effects of noxious deep somatic and noxious visceral manipulations on arterial pressure and heart rate were measured. The noxious visceral manipulations evoked substantial and sustained falls in arterial pressure (15–45 mmHg), and heart rate (75–100 bpm), whereas the depressor and bradycardiac effects of the noxious deep somatic manipulations were weaker, not as sustained, or entirely absent. As similar distributions and numbers of both increased and decreased Fos-like IR cells were observed after each of the deep noxious manipulations, it follows that the deep noxious evoked increases and decreases in Fos expression were not secondary to the evoked depressor or bradycardiac effects. © 1996 Wiley-Liss, Inc.     

Bulbar influences on the periaqueductal gray. Potential role in nociception

Unit activity was recorded from 96 neurons in the periaqueductal gray (PAG) in response to focal electrical stimulation of the lateral reticular nucleus (LRN) and the nucleus gigantocellularis (NGC), in anesthetized, curarized rats. Consistent with anatomical studies showing direct projections from these nuclei to PAG, short latency excitatory responses (less than 5 ms) were found in 63 neurons and inhibition of the activity in 28 neurons. Peripheral noxious heat stimulation was effective in altering the activity in 36 of these neurons (38%). The LRN and NGC stimuli inhibited the noxious evoked responses in 26 of these neurons. The inhibition could also be induced when the dorsolateral funiculi (DLFs) were cut. These results indicate that LRN and NGC can have a direct influence on PAG neurons, which are probably involved in the processing of noxious information.     

Effects of periaqueductal gray and raphe magnus stimulation on the responses of spinocervical and other ascending projection neurons to non-noxious inputs

Experiments were performed in cats anesthetized with α-chloralose to examine the effects of stimulating in the periaqueductal gray (PAG) and nucleus raphe magnus (NRM) on the responses of spinocervical cells and unidentified ascending projection neurons to non-noxious peripheral stimuli. Peripheral stimuli consisted of low amplitude sinusoidal displacements applied to either the glabrous skin or the hairy skin of the neuron's receptive field. Stimulating in either the periaqueductal gray or nucleus raphe magnus reduced the impulse activity of most neurons in both groups. By applying brainstem stimuli at various phases of the sinusoidal peripheral stimulus, it was demonstrated that the effects of stimulating either the PAG or NRM on the responses of both types of neurons was dependent on the timing of the electrical stimuli relative to the peripheral input. The effects of stimulating in the PAG and NRM on the responses of these cells to non-noxious stimuli were reversibly blocked by naloxone. It was concluded that stimulating in the nucleus raphe magnus and in the periaqueductal gray can produce dramatic modifications in the responses of spinocervical cells and unidentified ascending projection neurons to non-noxious peripheral stimuli, suggesting a role for these descending systems in non-noxious information processing.     

Antinociception induced by PAG-microinjected dipyrone (metamizol) in rats: involvement of spinal endogenous opioids

Dipyrone microinjection into the periaqueductal gray matter (PAG) elicits antinociception in rats by activating endogenous opioidergic circuits in PAG and the rostral ventromedial medulla. We have now found that endogenous opioids in the spinal cord are also involved. Responses of dorsal spinal neurons to noxious stimulation of a hindpaw were diminished (to 38–44%) by dipyrone microinjection (100 μg/0.5 μl) into the PAG. This was abolished by application of naloxone (50 μg/50 μl) to the spinal cord. The fact that dipyrone, a non-opioid analgesic, activates opioidergic circuits may be clinically important.     

Connections of the hypothalamic paraventricular necleus with the neurohypophysis, median eminence, amygdala, lateral septum and midbrain periaqueductal gray: An electrophysiological study in the rat

Extracellular recordings were obtained from 555 paraventricular (PVN) nucleus neurons in pentobarbital-anesthetized male rats. Cells were examined for their spontaneous activity patterns and response to single 1-Hz electrical stimulation of the neurohypophysis, median eminence, amygdala, lateral septum (LS) and midbrain periaqueductal gray (PAG).Neurohypophyseal stimulation evokedantidromic activation from 109 neurons. Among spontaneouly active neurohypophyseal neurons, evidence of a recurrent inhibitory pathway usually required pituitary stimulus intensities twice threshold for antidromic activation. Orthodromic excitatory or inhibitory responses followed amygdala and LS stimulation, but not PAG stimulation. The amygdala influence was predominantly inhibitory to ‘phasic’ (putative vasopressin-secreting) PVN neurohypophyseal neurons. Neurohypophyseal stimulation evokedorthodromic responses from 124 PVN cells; some of these neurons were also responsive to stimulation in other sites.Median eminence stimulation evoked antidromic responses from 37 PVN neurons; some of these cells also displayed phasic activity but not evidence for recurrent inhibition. Twelve cells in this group were also activated antidromically from both the median eminence and the neurohypophysis; collision tests suggest that the median eminence innervation may be an axon collateral of a neurohypophyseal pathway. Amygdala stimulation was inhibitory to some cells in this category.Amygdala, LS and PAG stimulation evoked antidromic activation from a small number of PVN cells, but none of these cells appeared to innervate more than one area, including the neurohypophysis, and none displayed phasic activity. Orthodromic responses were recorded among other PVN neurons after stimulation in these sites; however, PAG stimulation was the least effective stimulation area.These observations provide additional electrophysiological data that confirm efferent PVN connections to all areas tested, afferent connections from amygdala and LS but not PAG, and the possibility for coordinated activity among PVN neurons through local recurrent or common afferent connections.     

Elevation of serum prostagladin E levels following electrical stimulation of the midbrain

Serum prostaglandin E(PGE) levels were measured in rats immediately following electrical stimulation of the mesencephalic periaqueductal gray (PAG) region and the nucleus raphe magnus (NRM) and compared to controls. An additional group received aspirin prior to PAG stimulation. A significant increase in serum PGE levels was found after stimulation of the PAG, but not the NRM. Aspirin inhibited the stimulation-induced increases in PGE.     

The effects of a distant noxious stimulation on A and C fibre-evoked flexion reflexes and neuronal activity in the dorsal horn of the rat

In the halothane-anaesthetized rat, the responses of 49 neurons in the lumbo-sacral cord and the reflex discharge in the common peroneal nerve following electrical stimulation of the sural nerve were recorded in order to study possible relations between neuronal events and reflex nerve discharges. A distant noxious stimulus (to activate Diffuse Noxious Inhibitory Controls (DNIC) of Le Bars et al.¹⁹) was used as a conditioning stimulus. Only the responses of neurons receiving an input from both A and C fibres were studied. The neurons were classified as class 1 (low threshold mechanoreceptive input only, n = 2), class 2 (nonnoxious and noxious inputs, n =34) or class 3 (responding to noxious stimuli only, n = 13). During conditioning stimulation the C fibre evoked discharge was inhibited in 32 out of 34 class 2 neurons. The A fibre-evoked discharge was simultaneously inhibited in 29 of these neurons. The main effect of the distant noxious stimulation on the C fibre evoked neuronal discharge was to decrease the discharge by a constant number of spikes, independent of the level of evoked activity. Only one class 3 neuron was inhibited during conditioning stimulation and none of the class 1 cells were influenced by DNIC. During conditioning stimulation the late and prolonged C fibre evoked reflex nerve discharge (latency 160–200 ms, duration up to several hundred ms) was strongly depressed. Concomitantly, a short-lasting reflex nerve discharge appeared over the interval 115–160 ms. This released reflex nerve discharge (RR) had a constant latency. There was no simultaneous change of the Aβ evoked reflex nerve discharge. After the end of the distant noxious stimulation the late C fibre evoked reflex nerve discharge (latency 160–200 ms) recovered. Concomitantly, the RR disappeared. The possibility that the class 2 neurons and the class 3 neurons are intercalated in different reflex pathways is discussed.     

Serotonergic projections to the caudal brain stem: a double label study using horseradish peroxidase and serotonin immunocytochemistry

Cells of origin of serotonergic and non-serotonergic projections to the caudal brain stem in the primate were examined using a double label technique. Following HRP injections into medullary raphe nuclei and the adjacent reticular formation double labeled cells were found in the dorsal raphe nucleus, the central superior nucleus and the ventrolateral tegmentum. Retrogradely labeled cells that did not stain for serotonin-like immunoreactivity were found primarily in the periaqueductal gray (PAG) and the mesencephalic and pontine reticular formation. The results are discussed in relation to the descending pathway(s) mediating the effects of PAG stimulation.     

Administration of MK-801 decreases c-Fos expression in the trigeminal sensory nuclear complex but increases it in the midbrain during experimental movement of rat molars

Various studies reported c-Fos expression in the neurons in the trigeminal sensory nuclear complex (TSNC) following experimental tooth movement, which implies pain transmission to the central nervous system. Meanwhile, MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was shown to markedly reduce the expression of c-Fos in the trigeminal subnucleus caudalis (Vc) following noxious stimulation but to enhance c-Fos expression markedly in other brain regions, i.e., the neocortex, dorsal raphe and thalamic nuclei. In the present study, we examined the nature of c-Fos expression in the brainstem including the TSNC and midbrain following administration of MK-801 and/or experimental movement of the rat molars. Twelve hours after the beginning of experimental tooth movement, c-Fos was expressed bilaterally in the superficial laminae of Vc (Vc I/II), dorsomedial areas of the trigeminal subnucleus oralis (Vodm) and rostro-dorsomedial areas of the trigeminal subnucleus oralis (Vor) with the ipsilaterally dominant distribution, but hardly in the periaqueductal gray (PAG), dorsal raphe nucleus (DR) and Edinger-Westphal nucleus (EW). Intraperitoneal administration of MK-801 (0.03, 0.3 and 3.0 mg/kg) prior to the onset of experimental tooth movement reduced c-Fos in the TSNC (Vc I/II, Vodm and Vor) but increased it in the nucleus raphe magnus (NRM), ventrolateral PAG (vl PAG), DR and EW. These results highly emphasize that during experimental tooth movement, a blockade of NMDA receptors induces neuronal suppression in the TSNC but increases neuronal activity in the descending antinociceptive system including the NRM, vl PAG, DR and EW.     

Dual alterations of thalamic nociceptive activity by stimulation of the periaqueductal gray matter.

Effects produced by electrical stimulation of the mesencephalic periaqueductal gray matter (PAG) on single nociceptive neurons of the somesthetic thalamus were studied in rats anesthetized with α-chloralose and urethane. Stimulation of the PAG excited the nociceptive neurons, and, although the probability of firing them with a single pulse was low, trains of pulses increased their preexisting activity considerably and lastingly. Poststimulus spike density histograms of the activity evoked by stimulation of the sciatic nerve displayed several peaks which have been analyzed previously. In brief, a short-latency, high-count peak was related to the intensity of stimulation (I peak); three to four long-latency, low-count peaks were characteristic of nociception (modality, or M peaks). PAG stimulation modified mainly the M peaks. With stimulation of the caudal portion of the PAG, fusion of the M peaks was observed and persisted. With stimulation of its rostral portion each M peak was augmented. At several PAG sites, however, increasing the stimulus frequency and pulse-train duration converted the augmentation effect into fusion of the M peaks. Thalamic neurons that relay tactile afferents were not fired by stimulation of the PAG, although after such a stimulation they began to fire spontaneously. These results parallel the dual behavioral effects previously observed with PAG stimulation. When repeated trains of pulses were used, analgesia was induced that outlasted the period of stimulation. However, with stimulation of the rostral PAG, behavioral agitation and lowering of the nociceptive thresholds were observed. It is likely that augmentation of the M peaks represents central sensitization to noxious stimulation, and fusion of the M peaks represents a conversion of pain into less pain-like sensations. These effects may be mediated via a pathway that connects the PAG with the ventrobasal and the parafascicular nuclei of the thalamus.