Spinal Transmission Of Nociceptive Information Research Articles

Progress in renin-angiotensin system and pain in the central nervous system

Recent studies have shown that angiotensin Ⅱ (AngⅡ) may act as a neurotransmitter or neuromodulator in the spinal transmission of nociceptive information. This review illustrated the action site of AngⅡ, the localization of AngⅡ receptors and the mechanism of angiotensin peptides involved in pain in the central nervous system, to review the relationship between renin-angiotensin system (RAS) and pain in the central nervous system and provide reference for the treatment of postoperative pain. RAS will become new targets for the treatment of postoperative pain, which needs to be further investigated. Key words: Angiotensin Ⅱ; Pain; Spinal cord

Involvement of p38 MAPK activation mediated through AT1 receptors on spinal astrocytes and neurons in angiotensin II- and III-induced nociceptive behavior in mice

We have previously demonstrated the possibility that angiotensin (Ang) II and its N-terminal metabolite Ang (1–7) act as neurotransmitters and/or neuromodulators in the spinal transmission of nociceptive information. Ang III, which is a C-terminal metabolite of Ang II, can also act on AT1 receptors, but its role in spinal nociceptive transmission remains unclear. Therefore, we examined the role of Ang III on the spinal nociceptive system in comparison with that of Ang II. Intrathecal (i.t.) administration of Ang III into mice produced a nociceptive behavior, which was dose-dependently inhibited by the co-administration of the AT1 receptor antagonist losartan and the p38 MAPK inhibitor SB203580, but not by the AT2 receptor antagonist PD123319, MEK1/2 inhibitor U0126 and JNK inhibitor SP600125. In addition, Ang III increased the phosphorylation of p38 MAPK in the dorsal lumbar spinal cord, which was inhibited by losartan. These effects were similar to those of observed with Ang II. The nociceptive behavior produced by Ang II or III was also attenuated by the administration of the astrocytic inhibitor l-α-aminoadipic acid, but not by the microglial inhibitor minocycline. Double immunohistochemical staining showed that spinal AT1 receptors were expressed on neurons and astrocytes, and that i.t. administration of either Ang II or III phosphorylated p38 MAPK in both spinal astrocytes and neurons. These results indicate that Ang III produces nociceptive behavior similar to Ang II, and suggest that the phosphorylation of p38 MAPK mediated through AT1 receptors on spinal astrocytes and neurons contributes to Ang II- and III-induced nociceptive behavior.

The intrathecal administration of losartan, an AT1 receptor antagonist, produces an antinociceptive effect through the inhibiton of p38 MAPK phosphorylation in the mouse formalin test

We have recently reported that an intrathecal (i.t.) administration of angiotensin II (Ang II) into mice induces a nociceptive behavior accompanied by the activation of p38 MAPK signaling via AT1 receptors (Nemoto et al., 2013, Mol. Pain 9, 38). These results suggested that Ang II participates in the facilitation of nociceptive transmission in the spinal cord. In the present study, we used formalin test to examine the effect of i.t.-administered losartan, an AT1 receptor antagonist, and determine whether Ang II acts as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information. When administered i.t. 5min before the injection of a 2% formalin solution into the plantar surface of the hindpaw, losartan (30–100nmol) produced a dose-dependent and significant antinociceptive effect during both the first and second phases of the test. In the superficial dorsal horn of the spinal cord (laminae I and II), the fluorescence intensities for Ang II and phospho-p38 MAPK were both significantly increased on the ipsilateral side 3min after the injection of formalin compared to saline-treated controls. Moreover, the increase of phospho-p38 MAPK fluorescence intensity was significantly inhibited by the i.t. administration of losartan (54.8nmol) 5min prior to formalin. These results indicate that losartan produces an antinociceptive effect through the inhibition of p38 MAPK phosphorylation in the mouse formalin test and that Ang II may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information.

P.2.a.013 Antidepressant treatment and prefrontal cortex-hippocampus connection inhibition: communicating vessels?

The spinal cord dorsal horn contains neural mechanisms which can greatly facilitate pain. It is well established that excitatory amino acids, aspartate and glutamate, are involved in the spinal transmission of nociceptive information and in the development of hyperalgesia. In the present study, intrathecal (i.t.) administration of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), a structural analog of l-glutamate, produced a dose-dependent behavioural syndrome characterized by caudally directed biting in mice. We demonstrated that peripheral pre-administration of the AMPA receptor antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX, 10–100 mg/kg s.c.) and 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3,4-dihydro-7,8-methylene-dioxy-5H-2,3-benzodiazepine-HCl (GYKI 53655, 3–10 mg/kg s.c.), and also of the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK 801, 0.3–1 mg/kg s.c.) reversed this effect. These findings suggest that the hyperalgesia induced by the i.t. injection of AMPA in mice involves the activation of both NMDA and non-NMDA excitatory amino acid receptor sites.

Angiotensin II Produces Nociceptive Behavior through Spinal AT1 Receptor-Mediated p38 Mitogen-Activated Protein Kinase Activation in Mice

BackgroundIt has been demonstrated that angiotensin II (Ang II) participates in either the inhibition or the facilitation of nociceptive transmission depending on the brain area. Neuronal Ang II is locally synthesized not only in the brain, but also in the spinal cord. Though the spinal cord is an important area for the modulation of nociception, the role of spinal Ang II in nociceptive transmission remains unclear. Therefore, in order to elucidate the role of Ang II in nociceptive transmission in the spinal cord, we examined the effect of intrathecal (i.t.) administration of Ang II into mice.ResultsI.t. administration of Ang II produced a behavioral response in mice mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by Ang II (3 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.1-0.3 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also inhibited dose-dependently by i.t. co-administration of losartan (0.3-3 nmol), an Ang II type 1 (AT1) receptor antagonist, and SB203580 (0.1-1 nmol), a p38 MAPK inhibitor. However, the Ang II type 2 (AT2) receptor antagonist PD123319, the upstream inhibitor of ERK1/2 phosphorylation U0126, and the JNK inhibitor SP600125 had no effect on Ang II-induced nociceptive behavior. Western blot analysis showed that the i.t. injection of Ang II induced phosphorylation of p38 MAPK in the lumbar dorsal spinal cord, which was inhibited by losartan, without affecting ERK1/2 and JNK. Furthermore, we found that AT1 receptor expression was relatively high in the lumbar superficial dorsal horn.ConclusionsOur data show that i.t. administration of Ang II induces nociceptive behavior accompanied by the activation of p38 MAPK signaling mediated through AT1 receptors. This observation indicates that Ang II may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information.

Influence of NMDA and non-NMDA antagonists on acute and inflammatory pain in the trigeminal territory: a placebo control study

NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated. Male Rattus norvegicus were pre-treated with topiramate (T) (n=8), memantine (M) (n=8), divalproex (D) (n=8) or isotonic saline solution (ISS) (n=10) intraperitoneally 30 minutes before the formalin test. Formalin 2.5% was injected into the right upper lip (V2 branch) and induced two phases: phase I (early or neurogenic) (0-3 min) and phase II (late or inflammatory) (12-30 min). For motor behavior performance we used the open-field test and measured latency to movement onset, locomotion and rearing frequencies, and immobility time. Pre-treatment of animals with M and D only attenuated nociceptive formalin behavior for phase II. T increased locomotion and rearing frequencies and reduced immobility time. Treatment with M increased immobility time and with D reduced locomotion frequency. Our results showed that the NMDA antagonist (M) is more potent than the non-NMDA antagonists (D and T) in the control of pain in the inflammatory phase. The non-NMDA topiramate improved motor performance more than did D and M, probably because T has more anxiolytic properties.

Role of Spinal Cav2.2 and Cav2.1 Ion Channels in Bladder Nociception

High voltage activated calcium channels have been implicated in nociceptive transmission in several animal pain models. To our knowledge this is the first study to evaluate the ability of various high voltage activated calcium channel blockers to inhibit the transmission of noxious stimuli from the bladder at the level of the spinal cord. The nociceptive response was measured by analyzing the visceromotor reflex and cardiovascular (pressor) responses to bladder distention. The role of Cav2.2 (N-type), Cav2.1 (P/Q-type) and Cav1 (L-type) calcium channels in bladder nociceptive reflex responses was examined using omega-conotoxin-GVIA, omega-agatoxin IVA/omega-conotoxin MVIIC and verapamil (Sigma-Aldrich), respectively. Female Sprague-Dawley rats were acutely instrumented with intrathecal catheters, carotid arterial and bladder cannulas. Needle electrodes were placed directly into the abdominal musculature to measure myoelectric activity subsequent to repeat phasic bladder distention at 60 mm Hg for 30 seconds at 3-minute intervals with the rats under 1% isoflurane. Drugs were administered by intrathecal injection 2 minutes before distention and responses were recorded for 15 minutes per dose. When administered intrathecally, omega-conotoxin-GVIA and omega-conotoxin MVIIC (10 microg/kg each) significantly attenuated reflex responses to noxious bladder distention to 12% and 65% of the maximal visceromotor reflex response, and to 45% and 59% of the control pressor response, respectively. However, agatoxin and verapamil were less effective. The study suggests that spinal Cav2.2 and Q-type Cav2.1 calcium channels contribute to acute bladder nociception, while Cav1 channels have a limited role.

Possible involvement of the spinal nitric oxide/cGMP pathway in vincristine-induced painful neuropathy in mice

The mechanisms that underlie the development of vincristine-induced painful neuropathy are poorly understood. The nitric oxide (NO)-cGMP pathway has been reported to be involved in the spinal transmission of nociceptive information. In the present study, we examined whether alterations in spinal nociceptive processing via the NO-cGMP pathway contribute to vincristine-induced painful neuropathy in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg 1 day after the measurement of pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latencies developed at 4 weeks after treatment. Pretreatment with l-arginine (30–300 mg/kg, s.c.), a substrate of NO synthase (NOS), dose-dependently increased the tail-flick latencies in vincristine-treated mice. The l-arginine-induced increase in tail-flick latencies in vincristine-treated mice was completely reversed by i.t. pretreatment with N G-nitro- l-arginine methyl ester ( l-NAME, 3–30 nmol), a NOS inhibitor. Furthermore, i.t. pretreatment with 8-bromoguanosine 3′, 5′-cyclic monophosphate (8-Br-cGMP, 0.3–3.0 nmol), a membrane-permeable cGMP analog, dose-dependently increased the tail-flick latencies in vincristine-treated mice. The contents of NO metabolites, cGMP and protein levels of neuronal NOS in the spinal cord in vincristine-treated mice were significantly reduced compared to those in vehicle-treated naive mice. These results indicate that dysfunction of the l-arginine/NO/cGMP cascade in the spinal cord may trigger vincristine-induced thermal hyperalgesia in mice.

Role of calcium channels in the spinal transmission of nociceptive information from the mesentery

Opioids, α 2-adrenoceptor agonists and blockers of voltage-gated calcium channels (VGCCs) have been attributed antinociceptive activity in various experimental set-ups. The present study tested the ability of morphine, clonidine and drugs acting at various VGCCs to inhibit the transmission of noxious stimuli from the mesentery at the level of the spinal cord. In rats under barbiturate anaesthesia traction of 20 g was applied to a bundle of mesenteric blood vessels. This caused immediate transient changes of mean arterial pressure that were taken as indication of nociception. Similar reflexes were elicited by applying 0.6% acetic acid to the same bundle of vessels. The reflexes were dose-dependently reduced by intrathecal administration of morphine or clonidine, but were left unaltered by intrathecal administration of verapamil, Bay-K 8644 or ω-conotoxin MVIIA. Neither verapamil nor Bay-K 8644 influenced clonidine-induced analgesia. Conotoxin markedly enhanced the effectiveness of all doses of clonidine against both types of mesenteric stimuli. Verapamil, Bay-K 8644, as well as conotoxin reduced the ability of morphine to inhibit mechanically evoked reflexes, while there was no statistically significant effect in chemonociception. These data suggest that, at the spinal level, both morphine and clonidine are effective drugs to decrease the cardiovascular changes caused by acute mesenteric pain. In the dorsal spinal cord neither L-type nor N-type VGCCs are responsible on their own for the transmission of noxious stimuli from the mesentery. Inhibition of N-type channels markedly augments the action of clonidine, whereas blocking either VGCC seems to inhibit antinociceptive mechanisms induced by morphine. It is suggested that in patients the combined administration of clonidine with ω-conotoxin MVIIA might lead to effective pain control with reduced side effects.

Amplification of spinal nociceptive transmission depends on the generation of nitric oxide in normal and carrageenan rats

It has been proposed that nitric oxide (NO) is involved in the spinal transmission of nociceptive information, particularly following the development of peripheral inflammation. In this electrophysiological study the ability of the nitric oxide synthase inhibitor 7-nitro indazole (7-NI), which does not block endothelial nitric oxide in vivo, to inhibit the electrically evoked responses of dorsal horn neurones recorded in both normal animals and in animals 3 h after the injection of carrageenan into the ipsilateral hind paw, was investigated. In both normal and carrageenan inflamed animals, 7-NI (1–100 μg), administered intrathecally, strongly inhibited the NMDA receptor mediated wind-up and post-discharge of the neurones, having relatively little effect on the acute C- or Aβ-fibre evoked activity of the neurones. This inhibitory action of 7-NI on the noxious evoked responses of the neurones was completely blocked by the prior intrathecal administration of 500 μg of l-arginine. Inflammation did not alter the effects of 7-NI since there was no difference in the dose-response curve between the normal and carrageenan animals. In normal animals, stimuli of sufficient duration/intensity to enable the activation of NMDA receptors to occur, shown in this study by the occurrence of wind-up, also lead to the generation of nitric oxide, which then participates in nociceptive transmission. These effects appear to be independent of the vascular effects of NO. Inflammation-induced changes could facilitate activation of spinal NMDA receptors, such that nitric oxide is now generated by stimuli previously sub-threshold for this event. Previous studies, reporting a unique role of NO in nociceptive transmission following the development of peripheral inflammation, may have resulted from inadequate stimuli in the normal animal.

Pharmacological characterization of AMPA-induced biting behaviour in mice

The spinal cord dorsal horn contains neural mechanisms which can greatly facilitate pain. It is well established that excitatory amino acids, aspartate and glutamate, are involved in the spinal transmission of nociceptive information and in the development of hyperalgesia. In the present study, intrathecal (i.t.) administration of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), a structural analog of l-glutamate, produced a dose-dependent behavioural syndrome characterized by caudally directed biting in mice. We demonstrated that peripheral pre-administration of the AMPA receptor antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo( F)quinoxaline (NBQX, 10–100 mg/kg s.c.) and 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3,4-dihydro-7,8-methylene-dioxy-5 H-2,3-benzodiazepine-HCl (GYKI 53655, 3–10 mg/kg s.c.), and also of the NMDA receptor antagonist 5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine maleate (MK 801, 0.3–1 mg/kg s.c.) reversed this effect. These findings suggest that the hyperalgesia induced by the i.t. injection of AMPA in mice involves the activation of both NMDA and non-NMDA excitatory amino acid receptor sites.

The spinal transmission of nociceptive information: modulation by the caudal medulla.

Multiple descending systems for pain control originate from the rostral medulla and midbrain. These systems are involved in the antinociceptive action produced by opioids. One category of descending inhibitory controls is activated specifically by noxious stimuli and has been termed diffuse noxious inhibitory controls. These controls have been described in both animal and man, but their supraspinal circuitry has not been fully localized. To determine the supraspinal level of integration of nociceptor activated controls and hence their potential relationships with previously described descending controls, we studied in halothane-anesthetized rats the effects of transections performed at various levels in the brainstem. The physiological properties of dorsal horn convergent neurons, including supraspinally-mediated inhibitory processes elicited by heterotopic noxious stimuli, i.e. diffuse noxious inhibitory controls, were not altered in rats in which the brainstem had been completely transected up to 200 microns caudal to the caudal end of the rostral ventromedial medulla. In contrast, the spontaneous activity of these neurons was significantly enhanced and the inhibitory phenomena significantly reduced in animals with transections more than 500 microns caudal to the caudal end of the rostral ventromedial medulla. These effects were not related to cardiovascular changes induced by the transections. These data indicate that some tonic descending inhibitory controls and diffuse noxious inhibitory controls depend upon connections in the caudal medulla. It is proposed that this area constitutes another level from which the transmission of nociceptive information can be modulated and that it acts co-operatively with previously described modulatory systems in the spinal cord and at more rostral levels of the brainstem.

Dorsal horn convergent neurones: negative feedback triggered by spatial summation of nociceptive afferents

In order to investigate the effects of spatial summation on the spinal transmission of nociceptive information, we compared in intact and spinal anaesthetized rats, responses of lumbar convergent neurones elicited by noxious heat stimuli applied to areas of the body much greater in size than their individual excitatory receptive fields, located distally on the hindpaw. Twenty-four neurones were recorded in each group of animals. For each neurone, 4 successive immersions of increasing areas (1.9–18 cm 2) of the ipsilateral hindpaw in a 48°C water bath (15-sec duration) were performed with 10-min intervals in a randomized and balanced order. In intact animals, the responses of convergent neurones progressively decreased when the area of noxious thermal stimulation reached and then exceeded approximately twice the area of their individual excitatory receptive fields. This decrease was highly significant for 18 cm 2 which represents approximately 10-fold the mean of the receptive field areas. Such a phenomenon was not observed for neurones recorded in spinal animals although their excitatory receptive field areas were not significantly different. These results suggest that the activation of a large population of nociceptive afferents triggers supraspinally mediated negative feed-back loop modulating the responses of convergent neurones.

Effects of heterotopic noxious stimuli on activity of neurones in subnucleus reticularis dorsalis in the rat medulla.

1. In anaesthetized rats, recordings were made in the medullary subnucleus reticularis dorsalis. Neurones with total nociceptive convergence (TNC) responded to percutaneous electrical stimuli with early and late peaks due to the activation of A delta and C fibres respectively, no matter which part of the body was stimulated. Neurones with partial nociceptive convergence (PNC) responded with an A delta peak regardless of which part of the body was stimulated, and with a C peak of activation from some, mainly contralateral, parts of the body. 2. All TNC neurones responded to noxious thermal stimulation of the limbs with a phasic discharge followed by tonic activity that lasted throughout the stimulation. Discharges elicited by applying stimuli simultaneously to both forepaws or to a hindpaw and a forepaw were lower than the individual responses to stimulation of a single limb. Similar negative interactions were observed in the responses of PNC neurones following noxious thermal stimulation of two paws. 3. In both neuronal populations, the simultaneous application of noxious thermal stimuli and microelectrophoretic application of D,L-homocysteic acid (DLH) induced responses of greater magnitude than those evoked by each stimulus alone. 4. TNC neurones responded to electrical stimulation of the contralateral hindpaw with A delta and C fibre responses. Noxious thermal stimuli applied to different areas of the body induced an excitatory response during the period that preceded the electrical stimulation, but an inhibition of both A delta and C fibre responses. By contrast, using a similar protocol, application of DLH induced a steady discharge in the period preceding the electrical stimulation and also in between the A delta and C fibre responses, which were not themselves inhibited. 5. The negative heterotopic influences in normal rats during simultaneous immersion of the ipsi- and contralateral hindpaws was strongly reduced in rats with bilateral lesions of the dorsolateral funiculi at the cervical level (C3-C4). 6. It is concluded that strong negative interactions elicited by heterotopic noxious stimuli are observed in the spinoreticular system. Such interactions do not occur at the subnucleus reticularis dorsalis level but are mediated by supraspinal structures which control, through the dorsolateral funiculi, the spinal transmission of nociceptive information.

Release of sensory neuropeptides in the spinal cord: Studies with calcitonin gene-related peptide and galanin

In anaesthetized cats, antibody microprobes were used to investigate the release of immunoreactive calcitonin gene-related peptide and galanin in the lower lumbar spinal cord. In the absence of applied stimulation, a basal release of both peptides was detected at the level of the substantia gelatinosa. This release of calcitonin gene-related peptide was not altered by innocuous thermal cutaneous stimulation nor by electrical stimulation of low-threshold myelinated primary afferent fibres, but was increased by noxious thermal or noxious mechanical cutaneous stimuli and by electrical stimulation of unmyelinated primary afferents. A simultaneous release of both calcitonin gene-related peptide and substance P was detected in the substantia gelatinosa region by the use of pairs of microprobes. In contrast, none of the peripheral stimulation procedures increased intraspinal galanin release. The results suggest that the spinal transmission of nociceptive information may involve the simultaneous release and action of several neuropeptides within the superficial layers of the dorsal horn.

Pentobarbital, in subanesthetic doses, depresses spinal transmission of nociceptive information but does not affect stimulation-produced descending inhibition in the cat

The present study evaluates the effect of systemic pentobarbital on the spinal transmission of nociceptive information and on stimulation-produced descending inhibition in the deeply anesthetized, paralyzed cat. Single neuronal responses to noxious skin heating were recorded extracellulary in the lumbar dorsal horn and found to be depressed by pentobarbital at subanesthetic doses (4.0, 8.0, 17.0 and 24.5 mg/kg) in a dose-dependent manner. At 0.5 and 1.5 mg/kg, depression by pentobarbital was positively correlated with the depth of the recording site in the spinal cord (laminae IV–VI) i.e., neurons in deeper laminae (V–VI) were attenuated, while neurons in lamina IV were unaffected. At all doses tested, pentobarbital failed to affect stimulation-produced descending inhibition from either the midbrain periaqueductal gray or the medullary nucleus raphe magnus. The present data furnish evidence for the antinociceptive potency of pentobarbital, they do not support the view that a ‘partial pharmacological spinal cord transection’ would attenuate stimulation-produced descending inhibition of nociceptive dorsal horn neurons.

Calcitonin: brainstem microinjection but not systemic administration inhibits spinal nociceptive transmission in the cat

In anaesthetized cats, nociceptive responses of lumbar dorsal horn neurons were studied during administration of salmon calcitonin (sCT). Systemic sCT administration (4–95IU/kg i.v.) produced no change in neuronal responses produced by noxious skin heating or by impulses evoked electrically in afferent C-fibres. Responses to skin heating were reduced during electrical stimulation in the brainstem, but the efficacy of this descending inhibition was not altered by systemic sCT administration. In contrast, noxious heat responses were clearly reduced by microinjection of sCT into the mesencephalic periaqueductal grey or the medullary raphe regions. These results suggest that calcitonin or a related peptide could act at specific brainstem sites to inhibit the spinal transmission of nociceptive information.

The inhibitory effects of thalamic stimulation on the spinal transmission of nociceptive information in the rat

Single unit recordings were made in the lumbar dorsal horn of the halothane anaesthetized rat. Trains of electrical stimuli applied to the ipsilateral and contralateral ventrobasal thalamic complex could powerfully inhibit the activities of both convergent cells and neurones responding only to noxious inputs. Other neuronal classes were not influenced by the stimulation. The noxious and tactile related activities of the convergent cells were reduced by the thalamic stimulation. Electrolytic lesions of nucleus raphe magnus markedly reduced the inhibitory influences. The relevance of these effects to the analgesic effects of thalamic stimulation in man and animals is discussed.

Methysergide and supraspinal inhibition of the spinal transmission of nociceptive information in the anaesthetized cat

In anaesthetized cats methysergide was administered while measuring tonically present supraspinal inhibition of excitation of lumbar dorsal horn neurones by cutaneous noxious stimuli or by impulses in unmyelinated primary afferents. In some experiments inhibition was produced by electrical stimulation near the medullary raphe. Administered electrophoretically either near the bodies of dorsal horn neurones, in the region of the substantia gelatinosa, or topically to the dorsal surface of the spinal cord, methysergide did not reduce supraspinal inhibition. Administered intravenously in doses of up to 2.0 mg/kg, methysergide depressed the spinal transmission of nociceptive information and reduced supraspinal inhibition. It was considered that this latter effect did not result from a blockade of the action of 5-HT released by descending fibres but rather from a depression of the firing of the cells of origin.

Prolonged depression of spinal transmission of nociceptive information by 5-HT administered in the substantia gelatinosa: antagonism by methysergide

Prolonged depression of spinal transmission of nociceptive information by 5-HT administered in the substantia gelatinosa: antagonism by methysergide