Besides generally accepted lower analgesic potencies of opioids in neuropathic pain, our recent pharmacological reports have demonstrated that the effectiveness of the micro-opioid receptor (MOR) agonists in neuropathy might depends upon the chemical/structural property of these compounds (alkaloid vs. peptides). Such findings prompted us to investigate the changes in MOR mRNA expression (estimated by PCR) as well as MOR functional activity (examined by [(35)S]GTPgammaS binding) in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) of neuropathic rats at different time points after sciatic nerve ligation. We found that the spinal MOR mRNA level and agonist-stimulated [(35)S]GTPgammaS binding were not affected by nerve injury. In contrast, down-regulation of MOR mRNA in the ipsilateral side of DRG developed 3 (approximately 63% reduction) and 14 (approximately 89% reduction) days after the ligation. The decrease was paralleled with pronounced reduction in the stimulation of [(35)S]GTPgammaS binding by morphine (approximately 37-39%). Thus, neuropathy-induced specific dysfunction of MOR to activate G-protein together with changes in the MOR synthesis might be related, at least in part, to diminish analgesic efficacy of morphine in neuropathic pain. Interesting observations from current studies are linked to endomorphins (EMs), which do not affect the G protein stimulation of MOR after nerve ligation. This intriguing property of EMs, together with previously reported high analgesic efficacy of these compounds indicate that chemically/structurally different MOR agonists, particularly morphine versus EMs, may differentially interact with receptors causing distinct pharmacological effects in chronic pain.