Research report A pharmacological study of the modulation of neuronal and behavioural nociceptive responses in the rat trigeminal region (original) (raw)
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Brain Research, 1995
Electrical stimulation of the brain, particularly in the periventricular grey areas, caused long-lasting increases in behavioural escape thresholds to heating and mechanical stimuli applied to the facial region of the rat. The brain stimulation selectively suppressed responses to noxious stimuli. Responses to non-noxious stimuli, evoked by low threshold brush, were unaffected. The same animals that were studied in the behavioural tests were then anaesthetized with urethane and the inhibitory effect of the same brain stimulation was studied in single neurones recorded in the caudal trigeminal nucleus. A clear correlation (rs = 0.63) emerged between degree of behavioural antinociception and the amount of inhibition seen in nociceptive neurones. In addition the mean duration of the inhibition (6 min) was similar to the mean duration of the antinociceptive effect (7.3 min). Other classes of non-nociceptive neurones were unaffected by the stimulation. The neurones were also studied using iontophoretically applied monoamine candidates for the inhibitory neurotransmitter, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). The profile of the effects of NA most closely fitted that of the inhibitory neurotransmitter. This profile was expressed in terms of depression and excitation of different classes of neurones, and by the duration of effects. The depressant effects could be antagonized by iontophoretic idazoxan. In addition clonidine induced long-lasting depression of firing. 5-HT was more likely than NA to excite nociceptive neurones and to depress non-nociceptive neurones. Only NA consistently elevated thermal response thresholds in a similar manner to that produced by brain stimulation. These results provide some support for the hypothesis that selective descending inhibition of nociceptive responses in neurones of the rat caudal trigeminal nucleus is mediated by NA, possibly by an action at α2-adrenoceptors.
Pain, 2000
NMDA-type glutamate receptors are involved in the generation and maintenance of altered pain states. In the present study, we examined the effect of an NMDA-glycine site antagonist, GV196771A [E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2carboxylic acid sodium salt], on responses to noxious stimuli both in normal rats and during peripheral mononeuropathy induced by chronic constriction injury (CCI) of the sciatic nerve. In one series of experiments, activity of nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus was recorded in response to pressure stimuli to the contralateral hindpaw. Intravenous injection (iv) of the glycine antagonist had no effect on these cells in normal rats. When tested in rats with CCI induced 2±3 weeks previously, however, GV196771A (0.125, 0.5 and 2.0 mg/kg) blocked responses to noxious stimulation in a dose-dependent and reversible manner. Morphine (0.5 mg/kg, iv) and the NMDA channel blocker MK801 (0.1 mg/kg, iv) suppressed noxious stimulus-evoked activity of VPL neurons in both normal and CCI-treated rats. MK801 also decreased the responses of non-nociceptive neurons to brush stimulation in both sets of animals, in contrast to the glycine antagonist which did not alter the responses of these cells. Similar results were obtained from a series of behavior experiments in which the latency for paw withdrawal from heat stimulation was measured in normal and CCI-treated rats. GV196771A (3 and 10 mg/kg) injected orally, reduced the hyperalgesic response in the treated rats but did not change the withdrawal latency in normal rats. Taken together, these ®ndings suggest that block of the NMDA receptor decreases nociceptive transmission in the thalamus and can modulate hyperalgesic states. GV196771A and glycine antagonists in general may represent innovative and safe agents for the treatment of neuropathic pain. q 2000 International Association for the Study of Pain. Published by Elsevier Science B.V.
European Journal of Pain, 2000
It is well documented that the descending endogenous analgesia system, including the periaqueductal gray (PAG) and the rostral ventral medulla (RVM), play an important role in modulation of nociceptive transmission and morphine-and cannabinoid-produced analgesia. Neurons in the PAG receive inputs from different nuclei of higher structures, including the anterior cingulate cortex (ACC). However, it is unclear if stimulation of neurons in the ACC modulates spinal nociceptive transmission. The present study has examined the effects of electrical stimulation and chemical activation of metabotropic glutamate receptors (mGluRs) in the ACC on a spinal nociceptive tail-flick (TF) reflex induced by noxious heating. Activation of the ACC at high intensities (up to 500 µA) of electrical stimulation did not produce any antinociceptive effect. Instead, at most sites within the ACC (n = 36 of 41 sites), electrical stimulation produced significant facilitation of the TF reflex (i.e. decreases in TF latency). Chemical activation of mGluRs within the ACC also produced a facilitatory effect. Descending facilitation from the ACC apparently relays at the RVM. Electrical stimulation in the RVM produces a biphasic modulatory effect, showing facilitation at low intensities and inhibition at higher intensities. The present study provides evidence that activation of mGluRs within the ACC can facilitate spinal nociception.
Life Sciences, 2008
Aims: Several physiological, pharmacological and behavioral lines of evidence suggest that the hippocampal formation is involved in nociception. The hippocampus is also believed to play an important role in the affective and motivational components of pain perception. Thus, our aim was to investigate the participation of cholinergic, opioidergic and GABAergic systems of the dorsal hippocampus (DH) in the modulation of nociception in guinea pigs. Main methods: The test used consisted of the application of a peripheral noxious stimulus (electric shock) that provokes the emission of a vocalization response by the animal. Key findings: Our results showed that, in guinea pigs, microinjection of carbachol, morphine and bicuculline into the DH promoted antinociception, while muscimol promoted pronociception. These results were verified by a decrease and an increase, respectively, in the vocalization index in the vocalization test. This antinociceptive effect of carbachol (2.7 nmol) was blocked by previous administration of atropine (0.7 nmol) or naloxone (1.3 nmol) into the same site. In addition, the decrease in the vocalization index induced by the microinjection of morphine (2.2 nmol) into the DH was prevented by pretreatment with naloxone (1.3 nmol) or muscimol (0.5 nmol). At doses of 1.0 nmol, muscimol microinjection caused pronociception, while bicuculline promoted antinociception. Significance: These results indicate the involvement of the cholinergic, opioidergic and GABAergic systems of the DH in the modulation of antinociception in guinea pigs. In addition, the present study suggests that cholinergic transmission may activate the release of endorphins/enkephalin from interneurons of the DH, which would inhibit GABAergic neurons, resulting in antinociception.
Pain, 1983
To determine whether noradrenaline (NA) is involved in the powerful tonic descending inhibition which exists on dorsal horn nociceptor-driven neurones, their response to noxious radiant heat was tested with drugs that decrease freserpine) or enhance (nisoxetine, desipramine) NA synaptic transmission. In animals that were depleted of NA by reserpine (1.0 mg/kg i.p.) the degree of tonic inhibition (as determined by comparing the response in the normal vs. cold block states of the cord) was greater when compared to controls. Conversely, the extent of tonic descending inhibition on these neurones was decreased after the intravenous administration of NA uptake blockers, nisoxetine HCI and desipramine HCl (6 mg/kg). Thus we conclude that NA is not involved in mediating, but rather appears to reduce this tonic descending inhibition.
Pharmacology Biochemistry and Behavior, 1986
ITH) administration of 5 /xg 6-hydroxydopamine (6-OHDA) in mice selectively lesioned descending catecholaminergic pathways. Uptake of :~H-noradrenaline (:~H-NA) into synaptosomes from the lumbar spinal cord was reduced by 95%, without any change in the uptake of '~C-5-hydroxytryptamine (J~C-5-HT). Synaptosomal uptake ofaH-NA and ~4C-5-HT in the brain was not altered. The nociceptive sensitivity was evaluated using the tail-flick, hot plate and formalin tests 3 and 14 days after injection of 6-OHDA. At day 3 hyperalgesia was found in the hot-plate test, unchanged response latency in the tail-flick test and hypoalgesia in the formalin test. At day 14 there were no statistically significant differences from controls in any of the tests. The present findings support the contention that catecholaminergic pathways participate in the tonic regulation of nociception in the spinal cord. However, while supraspinally integrated responses to acute thermal pain, as measured with the hot-plate test, are inhibited by these pathways, responses to prolonged chemical pain are enhanced. Catecholamines 6-Hydroxydopamine Nociception Spinal cord
Pain, 1992
Recent anatomical evidence indicates that the pontine A7 catecholamine cell group provides the major noradrenergic innervation of the spinal cord dorsal horn (laminae I-IV>. The experiments described in this report were designed to determine if these neurons modulate nociception at the level of the spinal cord. To this end, the antinociceptive effect of electrical stimulation applied at various sites along several tracks through the dorsolateral pontine tegmentum was determined in lightly anesthetized rats. The latency of the withdrawal response of the hind feet to noxious radiant thermal stimulation applied to the dorsal surface was used as a measure of nociception. The results indicated that the most potent and consistent antinociception was produced at sites near the A7 cell group. In addition, intrathecal injection of a-noradrenergic antagonists blocked the antinociception produced by electrical stimulation at sites near the A7 group. These observations indicate that the antinociception produced by stimulation near the A7 cell group was mediated by spinally projecting noradrenergic neurons. The results of these experiments provide evidence that pontospinal noradrenergic neurons located in the A7 cell group are important components of the descending neuronal system that modulates nociception.
Brain Research Bulletin, 2014
The dorsal raphe nucleus (DRN) is involved in the control of several physiological functions, including nociceptive modulation. This nucleus is one of the main sources of serotonin to the CNS and neuromodulators such as opioids and GABA may be are important for its release. This study evaluated the influence of serotonergic, GABAergic and opioidergic stimulation, as well as their interactions in the DRN, on vocalization nociceptive response during a peripheral noxious stimulus application in guinea pigs. Morphine (1.1 nmol), bicuculline (0.50 nmol) and alpha-methyl-5-HT (1.6 nmol) microinjection on the DRN produces antinociception. The antinociception produced by morphine (1.1 nmol) and alpha-methyl-5-HT (1.6 nmol) into the DRN was blocked by prior microinjection of naloxone (0.7 nmol). The alpha-methyl-5-HT effect blocked by naloxone may indicate the existence of 5-HT 2A receptors on enkephalinergic interneurons within the dorsal raphe. Pretreatment with muscimol (0.26 nmol) also prevented the antinociceptive effect caused by morphine (1.1 nmol) when administered alone at the same site, indicating an interaction between GABAergic and opioidergic interneurons. The antinociception produced by bicuculline (0.5 nmol) in the DRN was blocked by prior administration of 8-OH-DPAT (0.5 nmol), a 5-HT 1A agonist. This may indicate that the 5-HT autoreceptor activation by 8-OH-DPAT at DRN effector neurons can oppose the bicuculline disinhibition effect applied to the same effectors. Thus, we suggest that 5-HT 2 receptor activation in the DRN promotes endorphin/enkephalin release that may disinhibit efferent serotonergic neurons of this present structure by inhibiting GABAergic interneurons, resulting in antinociception.
Behavioural Brain Research, 1995
The effects of 5-hydroxytryptamine (5-HT) and ligands selective for particular 5-HT receptor subtypes on the transmission of nociceptive information in the spinal cord are complex. In these studies, we have focused on their interactions with two endogenous mediators of pain suppression, noradrenaline (NA) and adenosine. Spinal antinociception by 5-HT is blocked by ~-adrenoreceptor antagonists and depletion of endogenous NA by 6-hydroxydopamine, while it is potentiated by blockade of NA reuptake with desipramine. These observations provide evidence for a 5-HT receptor-mediated increase in the release of NA from the spinal cord. This action appears to be due to activation of a 5-HTx-like receptor as it is mimicked by some 5-HT1 receptor ligands (mCPP, TFMPP and 5-Me-O-DMT), but not by DOI (5-HT2) or 2-Me-5-HT (5-HT3). An additional component of 5-HT action is via release of adenosine. Antinociception by 5-HT is blocked by the adenosine receptor antagonist 8-phenyltheophyUine, and 5-HT has been shown to release adenosine from the spinal cord in in vitro and in vivo paradigms. Methylxanthine-sensitive antinociception is seen with some 5-HT1 receptor ligands (CGS 12066B, mCPP), but not with others or with DOI or 2-Me-5-HT. Further characterization of the 5-HT receptor subtype involved in adenosine release will require the use of additional approaches.
The Journal of Physiological Sciences
Mediodorsal thalamic nucleus (MD) is a critical relay of nociception. This study recorded responses of MD neurons to noxious mechanical and thermal stimuli in isoflurane anesthetized rats. We found the threshold of noxious mechanical stimulation was 141 gw and that of noxious heat stimulation was 46 °C. A significantly higher percentage of noxious inhibitory neurons were found in the medial and central part of the MD, whereas a higher percentage of noxious excitatory neurons were found in the lateral part of the MD and adjacent intralaminar nuclei. The differential distribution of excitatory and inhibitory neurons implies functional differentiation between the medial and lateral part of the MD in nociception processing. Furthermore, by an analysis of the stimulus-response function (SRF), we found 80% of these excitatory neurons had a step-function or hat-shape-like SRF. This suggests that most of the MD neurons may serve as a system to distinguish innocuous versus noxious stimuli.