Mechanisms that mediate opioid potentiation in the rostral ventromedial medulla

The antinociceptive and antihyperalgesic actions of DAMGO and DELT, mu (MOR) and delta (DOR) opioid receptor agonists, respectively, microinjected in the rostral ventromedial medulla (RVM) are increased 4 hr, 4 d, and 2 wk after injection of complete Freund's adjuvant (CFA) in the hindpaw. Initial work highlighted the contribution of endogenous enkephalins; however, other mechanisms are likely involved. Therefore, this work investigated additional mechanisms underlying opioid potentiation in the RVM during persistent inflammatory nociception.; The first aim determined whether persistent inflammatory nociception increases MOR or DOR number or binding affinity in the RVM. Receptor radioligand binding assays in RVM membrane homogenates showed there was no increase in MOR number (Bmax) or binding affinity ( Kd) in the RVM 4 hr, 4 d, or 2 wk after CFA or saline injection. No appreciable [3H]-DELT specific binding was detected in the RVM of CFA- or saline-treated rats at any time point. Therefore, increased MOR number or binding affinity in the RVM does not contribute to opioid potentiation during persistent inflammation.; The second aim determined whether persistent inflammatory nociception increases MOR or DOR function at coupling to G proteins in the RVM. DAMGO and DELT [35S]-GTPgammaS stimulation assays in RVM membrane homogenates showed that there was no change in the efficacy (E max) or potency (EC50) of DAMGO to induce G protein coupling 4 hr, 4 d, or 2 wk after CFA or saline injection. No appreciable [35S]GTPgammaS stimulation was evident for DELT in the RVM of CFA- or saline-treated rats at any time point. Therefore, increased MOR function in the RVM does not contribute to opioid potentiation during persistent inflammation.; The third aim characterized DAMGO and DELT interaction in the production of antinociception in the RVM of naive rats. When DELT is the predominate component of a concurrently-administered combination, DELT and DAMGO interact additively. When DELT and DAMGO are coadministered in equal proportions, they exhibit a synergistic interaction. Thus, opioid potentiation may be mediated by an additive or synergistic interaction between endogenous enkephalins and exogenous opioids during persistent inflammatory nociception. Either result is consistent with potentiation of intra-RVM DELT or DAMGO during persistent inflammation.