The analgesic effects of supraspinal mu and delta opioid receptor agonistsare potentiated during persistent inflammation

This study examined the antihyperalgesic and antinociceptive effects of opi oid receptor agonists microinjected in the rostral ventromedial medulla (RV M) of rats 4 hr, 4 d, and 2 weeks after the induction of an inflammatory in jury by injection of complete Freund's adjuvant (CFA) in one hindpaw. Nocic eptive sensitivity of the ipsilateral, inflamed and the contralateral, unin flamed 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, w as enhanced 4 d and 2 weeks after injury. The antinociceptive potency of DA MGO, determined for the contralateral, uninflamed hindpaw, was also progres sively enhanced 4 hr, 4 d, and 2 weeks after injury. The magnitude of enhan cement paralleled the chronicity of the injury. The greatest potentiation o ccurred 2 weeks after injury when the ED50 value of DAMGO in CFA-treated ra ts was one-tenth that in saline-treated rats. The antihyperalgesic and anti nociceptive effects of the d opioid receptor agonist [D-Ala(2),Glu(4)]delto rphin were also increased 2 weeks after injury. These results indicate that peripheral inflammatory injury alters the pharmacology of excitatory and i nhibitory 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 sit e 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 su ppress nociceptive responses of the contralateral, uninflamed hindpaw.