cinanserin and Pain

Simultaneous single-unit and intracortical activity were recorded from neocortical neurons in urethane-anaesthetized rats to investigate the role of serotonin (5-HT) in modifying cortical excitability. Units, at a depth of 775-1100 microns from the pial surface, discharged in a burst-pause pattern that was correlated with slow wave activity. Application of noxious somatic stimulation resulted in cortical desynchronization and altered the pattern of unit activity such that firing was continuous, i.e., the pauses were eliminated. Intravenous administration of the mixed 5-HT1C/5-HT2 antagonists (cinanserin, cyproheptadine, ketanserin, and ritanserin) prevented both desynchronization and the change in unit activity induced by noxious stimulation within 2.5-15 min of the injection. The basic pattern of burst-pause activity remained intact, but the number of spikes per burst was typically reduced, whereas interburst intervals were increased. Iontophoretic application of these antagonists onto cortical neurons resulted in actions similar to those observed following systemic administration. Intravenous and iontophoretic application of m-trifluomethylphenylpiperazine (5-HT1C agonist, 5-HT2 antagonist) resulted in actions indistinguishable from those observed with the above antagonists, from which we conclude 5-HT2 and not 5-HT1C receptors mediate the alteration in unit activity observed with noxious stimulation. The results are discussed with respect to an interaction between N-methyl-D-aspartate and 5-HT2 receptors leading to the enhanced unit activity observed with noxious stimulation.

Topics: Animals; Cerebral Cortex; Cinanserin; Cyproheptadine; Iontophoresis; Ketanserin; Male; Microelectrodes; Neurons; Pain; Physical Stimulation; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Thresholds to noxious heat stimulation were increased following microinjection of zimelidine, an inhibitor of 5-hydroxytryptamine (5-HT) re-uptake, into the nucleus raphe magnus (NRM) of rats. Pretreatment with intraperitoneally given cinanserin reduced this effect but pretreatment with intraperitoneally given phenoxybenzamine did not. Fenfluramine, which causes the release of 5-HT from synaptic terminals also elevated nociceptive thresholds following microinjection into NRM. Subanalgesic doses of morphine or zimelidine elevated nociceptive thresholds when microinjected together into NRM. The elevation of nociceptive threshold produced by microinjection of morphine into NRM was reduced by simultaneous microinjection of cinanserin into NRM. Cinanserin alone had no effect when microinjected into NRM. These findings suggest that inhibition of the re-uptake of 5-HT in NRM can elevate nociceptive thresholds and that there may be an interaction between the effects of morphine and 5-HT in NRM.

Topics: Animals; Brain Stem; Cinanserin; Hot Temperature; Male; Morphine; Pain; Phenoxybenzamine; Raphe Nuclei; Rats; Rats, Inbred Strains; Sensory Thresholds; Serotonin; Zimeldine

The effects of the serotonin precursor 5-HTP, were determined in a behavioral DNIC paradigm (increase in vocalization threshold after intraperitoneal injection of the algogenic agent, phenylbenzoquinone). This counter-irritation phenomenon was strongly potentiated by 5-HTP, such potentiation being blocked by the 5-HT receptor blocker, cinanserin. These results are in keeping with those of our recent single unit work in dorsal horn convergent neurons.

Topics: 5-Hydroxytryptophan; Animals; Benzoquinones; Cinanserin; Cinnamates; Drug Synergism; Electric Stimulation; Male; Models, Psychological; Pain; Quinones; Rats; Rats, Inbred Strains; Sensory Thresholds; Vocalization, Animal

The involvement of serotonergic mechanisms in diffuse noxious inhibitory controls (DNIC) acting on dorsal horn convergent neurones has been studied in the anaesthetized rat. 35 neurones activated by transcutaneous electrical stimulation of their hindpaw receptive fields giving clear large A-fibre and C-fibre responses were recorded. These activities were conditioned by DNIC, evoked by either noxious heat applied to the tail or noxious pinch of the nose. Cinanserin (4 mg/kg i.v.) and metergoline (5 mg/kg i.v.), serotonin (5-HT) receptor blockers, strongly reduced the inhibitory effects of DNIC whilst having no significant effect on the non-conditioned responses. 5-Hydroxytryptophan, a precursor of 5-HT synthesis, significantly potentiated the effect of DNIC. These results indicate an important role for descending serotonergic pathways in DNIC. The functional role of this system is discussed.

Topics: 5-Hydroxytryptophan; Animals; Brain Stem; Cinanserin; Male; Metergoline; Neural Inhibition; Neural Pathways; Pain; Rats; Rats, Inbred Strains; Serotonin; Spinal Cord

Intracerebral administration of morphine into either nucleus reticularis paragigantocellularis (NRPG) or nucleus raphe magnus (NRM) of rats produced analgesia, as measured by the tail flick test. NRPG was more sensitive to morphine and the effect was dose dependent. The narcotic antagonist naloxone blocked these analgesic effects of morphine. The effect of intracerebral injection of naloxone on the analgesia produced by systemically administered morphine was examined. Morphine was administered subcutaneously (2.86 mg/kg) and naloxone was microinjected 35 min later. Microinjection of 5 micrograms of naloxone into NRM was found to be more effective in reversing in analgesia produced by morphine than naloxone microinjected into more lateral sites, including NRPG. Lesions of NRPG did not attenuate the analgesia produced by systemically administered morphine, whereas lesions of NRM did attenuate this analgesia. The analgesia produced by morphine administered into NRPG was blocked by lesions of NRM. Cinanserin, a serotonergic blocker, blocked the effects of morphine microinjected into NRM but not effects of morphine injected into NRPG. Phenoxybenzamine partially blocked the effects of morphine injected into NRPG but not the effects of morphine injected into NRM. These results show that both nuclei are sensitive to morphine, exert their effects by different synaptic mechanisms and that NRPG does not make an appreciable contribution to the analgesia produced by systemically administered morphine.

Topics: Analgesia; Animals; Cinanserin; Male; Microinjections; Morphine; Naloxone; Nociceptors; Pain; Phenoxybenzamine; Rats; Rats, Inbred Strains; Spinal Cord

Intensely noxious peripheral stimuli of the anaesthetized rat produce two changes in the activity of convergent dorsal horn units: the segmental neuronal pool is activated, while all other convergent neurones are inhibited. These Diffuse Noxious Inhibitory Controls (DNIC) are highly potent (60-80% inhibition) and suppress all convergent neuronal activity, whether spontaneous or evoked by noxious or nonnoxious stimuli. On the other hand, they have no effect on other dorsal horn cell types, including noxious-only and proprioceptive units. The "DNIC" circuits include at least one supraspinal relay since DNIC is not seen in spinal animals. Furthermore, they are greatly reduced by lesions of the Nucleus Raphé Magnus (NRM). It has been shown that this nucleus massively projects onto the spinal cord, in particular onto the dorsal horn, and that stimulation of the NRM results in convergent unit inhibition of the same degree of magnitude as with DNIC. The role of serotonergic mechanisms in DNIC can be demonstrated pharmacologically: pCPA pre-treatment (3 daily I.P. injections, 300 mg/kg) or cinanserin (4 mg/kg I.V.) both result in a potent decrease (50-80%). We have proposed that the nociceptive message from the convergent units could result in a contrast between activity of the activated segmental pool and silence of the remaining convergent units. If this hypothesis can be verified, then some raphé nuclei and brain stem serotonergic pathways may function as filters in the detection of nociceptive messages, allowing extraction of information from somatic background activity including the firing from peripheral mechanoreceptors. While superficially paradoxical in fact our hypothesis fits well with the observation of profound analgesia following NRM stimulation: indeed, this hypothetical contrast would be completely eliminated by NRM stimulation since both neuronal pools would then be inhibited.

Topics: Animals; Brain Stem; Cinanserin; Electric Stimulation; Neurons; Nociceptors; Pain; Raphe Nuclei; Rats; Receptors, Serotonin; Serotonin; Spinal Cord; Synaptic Transmission

Topics: Animals; Brain Mapping; Cerebral Aqueduct; Cinanserin; Cinnamates; Male; Methysergide; Morphine; Pain; Rats; Serotonin