Date Available

8-26-2013

Year of Publication

2013

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Physiology

First Advisor

Dr. Bradley K. Taylor

Abstract

Injury causes increased pain sensation in humans and animals but the mechanisms underlying the emergence of persistent pathological pain states, which arise in the absence of on-going physical damage, are unclear. Therefore, elucidating the physiological regulation of such intractable pain is of exceptional biomedical importance. It is well known that endogenous activation of µ-opioid receptors (MORs) provides relief from acute pain but the consequences of prolonged endogenous opioidergic signaling have not been considered. Here we test the hypothesis that the intrinsic mechanisms of MOR signaling promote pathological sensitization of pain circuits in the spinal cord. We found that tissue inflammation produces agonist-independent MOR signaling in the dorsal horn of the spinal cord, which tonically represses hyperalgesia for months, even after complete recovery from injury and re-established normal pain thresholds. Disruption of this constitutive activity with MOR inverse agonists reinstated pain and precipitated cellular, somatic and aversive signs of physical withdrawal. This phenomenon required N-methyl-D-aspartate receptor activation of calcium-sensitive adenylyl cyclase type 1. Thus, we present a novel mechanism of long-lasting opioid analgesia that regulates the transition from acute to chronic pain while, in parallel, generates physical dependence. In conclusion we propose that the prevalence of chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control.

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