Rationale: The synthesis and release of met-enkephalin and β-endorphin, endogenous ligands for δ-opioid peptide receptors (DOPrs), are altered following nicotine administration and may play a role in nicotine addiction.Objectives: To investigate the consequences of altered opioidergic activity on DOPr expression, coupling, and function in striatum during early nicotine withdrawal.Methods: Mice received nicotine-free base, 2 mg/kg, or saline, subcutaneously (s. c.), four times daily for 14 days and experiments performed at 24, 48, and 72 h after drug discontinuation. DOPr binding and mRNA were evaluated by [³H]naltrindole autoradiography and in situ hybridization. DOPr coupling and function were investigated by agonist pCl-DPDPE-stimulated [³⁵S]GTPγS binding autoradiography and inhibition of adenylyl cyclase activity.Results: During nicotine withdrawal DOPr binding was unaltered in caudate/putamen (CPu) and nucleus accumbens (NAc) shell and core. Receptor mRNA was slightly increased in the shell at 72 h, but significant elevations were observed in prefrontal cortex and hippocampus. pCl-DPDPE-stimulated [³⁵S]GTPγS binding was attenuated in NAc, but not CPu. In the shell, binding was decreased by 48 h and remained decreased over 72 h; while in the core, significant reduction was seen at 72 h. Basal adenylyl cyclase activity was suppressed in striatum at 24 h, but recovered by 48 h. DOPr stimulation with pCl-DPDPE failed to inhibit adenylyl cyclase activity at 24 h and produced attenuated responses at 48 and 72 h.Conclusions: These observations suggest that DOPr coupling and function are impaired in the NAc during nicotine withdrawal. DOPr desensitization might be involved in the affective component of nicotine withdrawal.