The analgesic effects of supraspinal μ and δ opioid receptor agonists are potentiated during persistent inflammation

This study examined the antihyperalgesic and antinociceptive effects of opioid receptor agonists microinjected in the rostral ventromedial medulla (RVM) of rats 4 hr, 4 d, and 2 weeks after the induction of an inflammatory injury by injection of complete Freund's adjuvant (CFA) in one hindpaw. Nociceptive sensitivity of the ipsilateral, inflamed and the contralateral, uninflamed hindpaws was determined by the radiant-heat paw withdrawal test. The antihyperalgesic potency of the mu opioid receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO), determined for the inflamed hindpaw, was enhanced 4 d and 2 weeks after injury. The antinociceptive potency of DAMGO, determined for the contralateral, uninflamed hindpaw, was also progressively enhanced 4 hr, 4 d, and 2 weeks after injury. The magnitude of enhancement paralleled the chronicity of the injury. The greatest potentiation occurred 2 weeks after injury when the ED50 value of DAMGO in CFA-treated rats was one-tenth that in saline-treated rats. The antihyperalgesic and antinociceptive effects of the d opioid receptor agonist [D-Ala(2),Glu(4)]deltorphin were also increased 2 weeks after injury. These results indicate that peripheral inflammatory injury alters the pharmacology of excitatory and inhibitory inputs that modulate the activity of RVM neurons in such a manner as to enhance the effects of opioid agonists in this region. These changes have ramifications not only for the alleviation of hyperalgesia at the site of injury but also for opioid-induced antinociception at sites remote to the injury as revealed by increases in the potency of opioid agonists to suppress nociceptive responses of the contralateral, uninflamed hindpaw.