Stanfa, Louise Claire; (1994) Electrophysiological studies on the pharmacology of altered spinal nociceptive mechanisms induced by inflammation in the rat. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The purpose of the in vivo electrophysiological experiments presented in this thesis was to investigate how the pharmacology of the spinal transmission and modulation of nociceptive messages following the development of peripheral inflammation compares with that in normal, non-inflamed animals. Recordings of convergent dorsal horn neurones were made in intact halothane anaesthetized rats, and unilateral inflammatory hyperalgesia was produced by the injection of carrageenan into the hind paw. Alterations in spinal nociceptive transmission occurred as the inflammation developed. 58% of the neurones tested showed enhanced responses to peripheral electrical stimulation; evidence of central sensitization. In contrast, the other neurones showed decreased responses, which were linked with high levels of N-methyl-D- aspartate (NMDA) receptor-mediated wind-up. The role of the NMDA receptor in spinal nociceptive transmission was found to be altered post-carrageen an, with evidence for facilitated activation of the receptor. The modulation of spinal nociceptive transmission following inflammation was studied using antinociceptive drugs, both opioid and non-opioid, to inhibit nociceptive responses. The mu opioid morphine showed a large increase in spinal potency following inflammation which was not seen with delta or kappa opioids, or the non-opioid analgesics tested. An investigation into the pharmacological systems in the spinal cord underlying this selective enhancement in the potency of morphine revealed the 'antiopioid' peptide cholecystokinin as a factor in this phenomenon. The descending noradrenergic system, which has the potential to synergize with the antinociceptive effects of mu opioids, was not involved. Changes in the endogenous spinal opioid systems after inflammation were also studied, revealing enhanced actions of the endogenous kappa opioid ligand dynorphin in the absence of any changes in the controls exerted by the enkephalins, the endogenous ligand at delta opioid receptors. Complex changes in the pharmacology of spinal sensory systems occur within hours of the development of inflammation.

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