Eicosanoid mediationmodulation in spinal nociceptive mechanisms in the normal rat and in a rat model of chronic pain

The studies presented in this thesis are concerned with physiological and neurochemical characterization of on-going and stimulation-elicited synaptic transmission of sensory information in the dorsal horn of the rat spinal cord.Historically, since the use of willow tree bark extract for pain relief, the recognition that it and related nonsteroidal anti-inflammatory drugs (NSAIDs) express their analgesic and anti-inflammatory effects by inhibiting cyclooxygenase (COX) and more recently the identification of two forms of COX, inducible (COX-2) and constitutive (COX-1), efforts have focussed on exploring the therapeutic potential of this class of drugs.In normal rats, the response to noxious peripheral stimulation involves at least two distinct discharge responses of dorsal horn neurones, an initial discharge which lasts only for the duration of the stimulus and a slowly-decaying afterdischarge which persists beyond the end of the stimulus. Innocuous mechanical stimulation produces excitation of dorsal horn neurones lasting only for the duration of the stimulus. Characterization of these excitatory responses reveals that the initial discharge in response to noxious or innocuous mechanical stimulation involves only limited activation of the eicosanoid pathway via COX, while the afterdischarge is sustained to a major extent via COX activation, at least in part by COX-2. On-going discharge seems not to involve activation of COX.An animal model of neuropathic pain was induced by implantation of a 2 mm polyethylene cuff around one sciatic nerve in rats. This lowers the nociceptive threshold in the von Frey hair test and induces spontaneous pain behaviour. In cuff-implanted rats, on-going activity is greater compared to that in normal rats. Furthermore, noxious mechanical stimulation evokes an afterdischarge response of dorsal horn neurones which is markedly greater than that in normal rats but the initial discharge is not different. Importantly, a switch in the response to innocuous mechanical stimulation is observed also such that an afterdischarge occurs after the end of the initial discharge, which is not seen in normal rats.Characterization of the synaptically-elicited responses in cuff-implanted rats to noxious and innocuous mechanical stimulation reveals that the initial discharge, and to a greater extent the afterdischarge, are subject to a COX-2-mediated or modulatory mechanism. The elevated on-going discharge in cuff-implanted rats may also be sustained via tonic COX-2 activity.These results demonstrate participation of unique and identifiable physiological and neurochemical mechanisms in the mediation and modulation of on-going and synaptically-elicited responses in the dorsal horn of the spinal cord in normal sensory processing and in sensory processing associated with peripheral neuropathy. Ultimately, the data in this thesis may advance understanding of the neurophysiological basis of chronic pain syndromes