Shared mechanisms for opioid tolerance and a transition to chronic pain

Abstract

Clinical pain conditions may remain responsive to opiate analgesics for extended periods, but such persistent acute pain can undergo a transition to an opiate-resistant chronic pain state that becomes a much more serious clinical problem. To test the hypothesis that cellular mechanisms of chronic pain in the primary afferent also contribute to the development of opiate resistance, we used a recently developed model of the transition of from acute to chronic pain, hyperalgesic priming. Repeated intradermal administration of the potent and highly selective μ,-opioid agonist, [D-Ala 2,N-MePhe 4,gly-ol]-enkephalin (DAMGO), to produce tolerance for its inhibition of prostaglandin E2 hyperalgesia, simultaneously produced hyperalgesic priming. Conversely, injection of an inflammogen, carrageenan, used to produce priming produced DAMGO tolerance. Both effects were prevented by inhibition of protein kinase Cε (PKCε). Carrageenan also induced opioid dependence, manifest as μ-opioid receptor antagonist (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2)-induced hyperalgesia that, like priming, was PKCε and Gi dependent. These findings suggest that the transition from acute to chronic pain, and development of μ-opioid receptor tolerance and dependence may be linked by common cellular mechanisms in the primary afferent. Copyright © 2010 the authors.