Disruption of the CRF(2) receptor pathway decreases the somatic expression of opiate withdrawal.
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.
Papaleo
Francesco
F
Unité de Nutrition et Neurosciences, Universités Bordeaux 1 et Victor Segalen Bordeaux 2, Talence, France.
Ghozland
Sandy
S
Ingallinesi
Manuela
M
Roberts
Amanda J
AJ
Koob
George F
GF
Contarino
Angelo
A
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
C101531:CRF receptor type 2; D009292:Narcotic Antagonists; D018019:Receptors, Corticotropin-Releasing Hormone; D003345:Corticosterone