Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats.
BACKGROUND
Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, shows similarities to dynorphin A (1-17) in structure and functions. Dynorphin and other kappa opioid receptor agonists have been shown to block cocaine sensitization.


OBJECTIVE
The present study was designed to examine the ability of OFQ/N to block cocaine-induced behavioral sensitization.


METHODS
Rats were habituated to testing chambers for 1 h, injected with artificial cerebrospinal fluid (aCSF) or OFQ/N (15 nmol) followed by saline or cocaine (20 mg/kg) and locomotor activity was measured for a further 1 h. Rats were treated similarly for the next 2 days except the dose of OFQ/N was doubled on each subsequent day. Rats were then challenged with cocaine (7.5 mg/kg) in the absence of OFQ/N on day 8. The specificity of OFQ/N's action was examined in the presence of J-113397 (30 nmol), an ORL-1 receptor antagonist. The ability of OFQ/N to block the context-independent component of cocaine sensitization was also tested wherein rats were treated in their home cages on days 1-3. Finally, the effect of intra-VTA OFQ/N administration on cocaine sensitization was examined.


RESULTS
Sensitization did not develop in rats repeatedly treated with OFQ/N, via either route of administration, prior to cocaine administration on days 1-3. The inhibitory effect of OFQ/N was not dependent on context and was blocked by pretreatment with J-113397.


CONCLUSIONS
Our results indicate that OFQ/N blocks cocaine-induced behavioral sensitization through activation of the ORL-1 receptor and that the VTA may be one of the substrates for this action of OFQ/N.
Lutfy
Kabirullah
K
Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
Khaliq
Imran
I
Carroll
F Ivy
FI
Maidment
Nigel T
NT
D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D007276:Injections, Intraventricular; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D001562:Benzimidazoles; D003042:Cocaine; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C402921:J 113397; C000722285:Oprl1 protein, rat