Opioids represent effective drugs for the relief of
pain, yet chronic
opioid use often leads to a state of increased sensitivity to
pain that is exacerbated during withdrawal. A sensitization of
pain-related negative affect has been hypothesized to closely interact with addiction mechanisms. Neuro-adaptive changes occur as a consequence of excessive
opioid exposure, including a recruitment of
corticotropin-releasing factor (CRF) and
norepinephrine (NE) brain stress systems. To better understand the mechanisms underlying the transition to dependence, we determined the effects of functional antagonism within these two systems on
hyperalgesia-like behavior during
heroin withdrawal utilizing models of both acute and chronic dependence. We found that passive or self-administered
heroin produced a significant mechanical
hypersensitivity. During acute
opioid dependence, systemic administration of the
CRF1 receptor antagonist MPZP (20 mg/kg) alleviated withdrawal-induced mechanical
hypersensitivity. In contrast, several functional
adrenergic system antagonists (
clonidine,
prazosin,
propranolol) failed to alter mechanical
hypersensitivity in this state. We then determined the effects of chronic MPZP or
clonidine treatment on extended access
heroin self-administration and found that MPZP, but not
clonidine, attenuated escalation of
heroin intake, whereas both drugs alleviated chronic dependence-associated
hyperalgesia. These findings suggest that an early potentiation of CRF signaling occurs following
opioid exposure that begins to drive both
opioid-induced
hyperalgesia and eventually intake escalation.