Contribution of endogenous enkephalins to the enhanced analgesic effects of supraspinal mu opioid receptor agonists after inflammatory injury

This study examined a mechanism responsible for the enhanced antihyperalges ic and antinociceptive effects of the mu opioid receptor agonist (ORA) [D-A la(2), NMePhe(4), Gly(5)-ol]enkephalin (DAMGO) microinjected in the rostrov entromedial medulla (RVM) of rats with inflammatory injury induced by injec tion of complete Freund's adjuvant (CFA) in one hindpaw, In rats injected w ith CFA 4 hr earlier, microinjection of the mu opioid receptor antagonist D -Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) in the RVM antagonized both t he marginal enhancement of the potency of DAMGO and its antinociceptive eff ect. The delta opioid receptor antagonist naltriben (NTB) was without effec t. In rats injected with CFA 2 weeks earlier, CTAP antagonized the effects of DAMGO to a lesser extent. However, NTB completely prevented the enhancem ent of the potency of DAMGO, whereas it did not antagonize DAMGO's antinoci ceptive effects. Microinjection of NTB alone, but not CTAP in the RVM of CF A-treated rats, enhanced the hyperalgesia present in the ipsilateral hindpa w and induced hyperalgesia in the contralateral, uninjured hindpaw. These r esults suggest that persistent inflammatory injury increased the release in the RVM of opioid peptides with preferential affinity for the delta opioid receptor, which can interact in a synergistic or additive manner with an e xogenously administered mu opioid receptor agonist. Indeed, the levels of [ Met(5)]enkephalin and [Leu(5)]enkephalin were increased in the RVM and in o ther brainstem nuclei in CFA-treated rats. This increase most likely presen ts a compensatory neuronal response of the CNS of the injured animal to mit igate the full expression of inflammatory pain and to enhance the antinocic eptive and antihyperalgesic effects of exogenously administered mu opioid r eceptor analgesics.