The activity of bulbospinal pathways that modulate pain sensitivity is altered during persistent inflammatory nociception. These changes have consequences for the actions of opioid receptor agonists. For example, the antihyperalgesic and antinociceptive effects of both mu and delta opioid receptor agonists are enhanced in the rostral ventromedial medulla (RVM) of rats with persistent inflammatory nociception. Prior work attributed this effect to an interaction between (1) exogenously administered DAMGO, mu opioid receptor agonist, and (2) endogenous enkephalins that act preferentially at delta opioid receptors and whose synthesis is upregulated in rats with persistent inflammatory nociception. This finding, however, does not address the cellular mechanisms that are responsible. We hypothesize that the enhancement of the effects of opioid agonists in the RVM may result from changes in the levels, mobilization, and/or affinity of mu or delta opioid receptors in the RVM as a consequence of persistent inflammatory nociception. To this end, we propose to determine whether persistent inflammatory nociception (1) increases protein levels of mu or delta opioid receptors in the RVM; (2) increases trafficking of delta opioid receptors to the plasma membrane from intracellular compartments of RVM neurons; and/or (3) increases the affinity and/or the efficacy of mu or delta opioid receptor agonists in the RVM. The collective findings of these studies will provide new information about plasticity in a brainstem region that plays a key role in pain modulation and opioid analgesia.
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| Sykes, Kenneth T; White, Stephanie R; Hurley, Robert W et al. (2007) Mechanisms responsible for the enhanced antinociceptive effects of micro-opioid receptor agonists in the rostral ventromedial medulla of male rats with persistent inflammatory pain. J Pharmacol Exp Ther 322:813-21 |
