Escape from the extremely aversive
opiate withdrawal symptoms powerfully motivates compulsive drug-seeking and drug-taking behaviors. The
corticotropin-releasing factor (CRF) system is hypothesized to mediate the motivational properties of
drug dependence. CRF signaling is transmitted by two receptor pathways, termed CRF(1) and CRF(2). To investigate the role for the CRF(2) receptor pathway in somatic
opiate withdrawal, in the present study we used genetically engineered mice deficient in the CRF(2)
receptor (CRF(2)-/-). We employed a novel, clinically relevant mouse model of 'spontaneous'
opiate withdrawal as well as a classical
opioid receptor antagonist (
naloxone)-precipitated
opiate withdrawal paradigm. To induce
opiate dependence, mice were treated with intermittent escalating
morphine doses (20-100 mg/kg, i.p.). We found that 8-128 h after the last
opiate injection, CRF(2)-/- mice showed decreased levels of major somatic signs of spontaneous
opiate withdrawal, such as paw
tremor and wet dog shake, as compared to wild-type mice. Similarly, challenge with
naloxone 2 h after the last
morphine injection induced lower levels of paw
tremor and wet dog shake in CRF(2)-/- mice as compared to wild-type mice. Despite the differences in somatic signs, wild-type and CRF(2)-/- mice displayed similar plasma
corticosterone responses to
opiate dosing and withdrawal, indicating a marginal role for the hypothalamus-pituitary-adrenal axis in the CRF(2) receptor mediation of
opiate withdrawal. Our results unravel a novel role for the CRF(2) receptor pathway in
opiate withdrawal. The CRF(2) receptor pathway might be a critical target of
therapies aimed at alleviating
opiate withdrawal symptoms and reducing relapse to drug intake.