Haley, Jane Elizabeth; (1991) An electrophysiological study in the rat on the role of central and peripheral mediators in prolonged nociception. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This in vivo pharmacological study has used electrophysiological techniques to investigate the mechanisms and control of prolonged nociception. Formalin injection into the receptive field was used as a prolonged stimulus and the activity of nociceptive neurones located within the spinal cord was recorded in the halothane anaesthetized intact rat. Acute electrically evoked activity of these neurones resulting from both A and C fibre inputs was used as a comparison. The response of dorsal horn neurones to formalin was biphasic and lasted about 60 minutes. The first peak firing began immediately following injection of the formalin and lasted for about 5 minutes. Following a period of inactivity the neurone once again started firing, usually about 25 minutes following the formalin administration and this second peak persisted for approximately 35-40 minutes. This profile of activity is very similar to the pain related behaviour observed in conscious animals following formalin administration. Correlations were sought between the electrically evoked properties of the neurones and their responses to formalin. Intravenous and intrathecal administration of mu opioids inhibited both peaks of the formalin response. Using peripheral and intrathecal administration of bradykinin and selective B1 and B2 receptor antagonists, evidence was provided for a role of the bradykinin B2 receptor in the peripheral generation of the second peak of the response. The role of excitatory amino acids within the spinal cord was investigated. The non-selective antagonist γ-D-glutamyl glycine (DOG) reduced both the electrically evoked A and C fibre responses and both peaks of the formalin response. Selective antagonists at the N-methyl-D-aspartate (NMDA) receptor, 5-DL-amino phosphonovaleric acid (AP5), ketamine and MK801 were administered intrathecally and intravenously. Ketamine reduced the 'wind up' of the neurones (the frequency dependent potentiation of dorsal horn neurone responses to repetitive C fibre stimulation) and all the compounds selectively reduced the second peak of the formalin response with little effect on the first peak. Nitric oxide (NO) has been implicated in both bradykinin and NMDA mediated events. An inhibitor of nitric oxide synthesis administered into the receptive field and intrathecally reduced both peaks of the formalin response whilst systemic administration resulted in a selective inhibition of the second peak. However, intrathecal administration of the NO precursor L-arginine unexpectedly reduced both the electrically evoked A and C fibre responses and both peaks of the formalin response. Although these results are suggestive of a role for NO in both peripheral and spinal mediation of nociceptive events, the high doses required, route dependent effects and contradictory result with L-arginine suggest the involvement of this molecule is complex. Whilst administration of selective mu and delta opioid agonists into the receptive field had no effect on either peak of the formalin response, a selective kappa opioid agonist inhibited both peaks of the formalin response whilst having no effect on the acute electrically evoked A or C fibre responses. Thus the peripheral generation of the formalin response involves the actions bradykinin, via the B2 receptor, during the second phase and this may also involve the generation of nitric oxide. The afferent input is mediated within the spinal cord by excitatory amino acids acting at non-NMDA receptors during the first peak of the response, but during the prolonged activity of the second peak NMDA receptor involvement becomes important as well. It is possible that the NMDA receptor may be responsible for amplifying the response. This formalin evoked activity within the spinal cord may also involve nitric oxide. The formalin response can be modulated by opioids acting at the spinal level and at the peripheral level where only the kappa receptor appears to be effective. These results indicate some of the mechanisms involved in the generation and transmission of prolonged nociception and may provide future directions for the development of novel analgesics.

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