Implications of persistent inflammatory pain for the actions of opioid analgesics

Substantial evidence obtained using rodent models of acute nociception indicates that the rostral ventromedial medulla (RVM) is involved in the modulation of nociception and is a key site for the production of antinociception by opioid receptor agonists. Although acute pain is an important medical concern, persistent pain has greater physiological, psychological and socioeconomic costs to the individual and society. Little is known about the ramifications of persistent nociception on the supraspinal neurons involved in the modulation of nociception. This thesis examined how the development and maintenance of a chronic inflammatory pain state affects the opioid pharmacology and neurochemistry of neurons in the RVM. Initial studies indicated that the induction of persistent inflammatory pain by the injection of complete Freund's adjuvant (CFA) in one hindpaw leads to an enhancement in both the antihyperalgesic and the antinociceptive effects of mu and delta opioid receptor agonists when administered into the RVM. Subsequent studies with selective antagonists revealed that persistent injury evokes a compensatory increase in endogenous opioid tone. This tone is responsible for an antihyperalgesic effect on its own that serves to mitigate the full expression of hyperalgesia induced by CFA. Further, the increased endogenous opioid tone at delta receptors provides a mechanism for the enhancement of the effects of the mu opioid receptor agonist. The apparently preferential involvement of delta receptors in the compensatory response suggests that there is an upregulation of enkephalinergic inputs to the RVM. This hypothesis was confirmed through the use of radioimmunoassay, which documented an increase in the levels of [Met5] and [Leu5]enkephalin within the RVM. The lack of a concomitant increase in the level of mRNA for preproenkephalin observed using Northern blot analysis suggests that this upregulation of peptides is independent of increased transcription of the mRNA. Taken together, these results suggest that persistent inflammatory pain evokes a compensatory upregulation of opioid tone in the RVM as part of a homeostatic mechanism to mitigate the full expression of hyperalgesia. This upregulation of endogenous opioid peptides appears to act coincidently, in an additive or synergistic manner, with exogenously administered opioid analgesics to enhance their antinociceptive and antihyperalgesic effects.