An antisense oligodeoxynucleotide to the mu opioid receptor attenuates cocaine-induced behavioral sensitization and reward in mice.
Numerous studies support a role for the endogenous opioid system in cocaine-influenced behavior. Few of these studies, however, selectively delineate a role for the mu opioid receptor (MOR) in this regard. This investigation examined if the MOR modulates cocaine-induced behavior in mice using a 17-base antisense oligodeoxynucleotide (AS ODN) directed against the MOR coding sequence 16-32. Specifically, cocaine-induced behavioral sensitization and conditioned reward were investigated. For the sensitization study, C57BL/6J mice received eight intermittent i.c.v. infusions of saline, mismatch oligodeoxynucleotide (ODN) (20 microg/4 microl) or AS ODN (20 microg/4 microl) over 20 days. Mice also received concomitant once daily i.p. injections of saline (4 ml/kg) or cocaine (15 mg/kg) for 10 days. There was a 7-day withdrawal period, after which all mice were challenged with cocaine (15 mg/kg) to test for behavioral sensitization. For the conditioned place preference (CPP) study, mice received five i.c.v. infusions of mismatch ODN or MOR AS ODN (days 1-5). An unbiased counterbalanced conditioning procedure was used where mice were conditioned with saline (4 ml/kg, i.p.) and cocaine (15 mg/kg, i.p.) on alternate days for four sessions (days 3-6). Mice were tested on day 7 for CPP. Immediately following testing, [3H]DAMGO (D-Ala2, N-Me-Phe4, Gly-ol5-enkephalin) receptor binding to brain homogenates was conducted. MOR AS attenuated cocaine-induced behavioral sensitization and conditioned reward. MOR AS ODN also reduced [3H]DAMGO binding. Collectively, these findings implicate the MOR as playing an important neuromodulatory role in the behavioral effects of cocaine in mice.
Hummel
M
M
Department of Pharmacology and the Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA. Hummelm2@wyeth.com
Schroeder
J
J
Liu-Chen
L-Y
LY
Cowan
A
A
Unterwald
E M
EM
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects; D004333:Drug Administration Routes; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D011859:Radiography / Q000379:methods; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012201:Reward; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D009294:Narcotics; D020319:Oligodeoxyribonucleotides, Antisense; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine