In vivo data on opioid receptor mRNA regulation after agonist exposure in the peripheral nervous system are lacking. Therefore, we studied the impact of morphine treatment on the regulation of mu-opioid receptor mRNA during behavioral signs of tolerance in rat peripheral sensory ganglia. Nineteen rats were treated in 2 groups with either morphine (10 mg/kg subcutaneously) or saline over 4 days, and a subset of rats received naloxone on the fifth day followed by either morphine injection on the sixth day or death to obtain dorsal root ganglia for mRNA analysis. Animals were tested on the hot plate during treatment days. To assess the levels of mu-opioid receptor mRNA, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used with the co-amplification of the "housekeeping" gene cyclophilin as internal control. Morphine treatment over 4 days induced tolerance as reflected on the hot-plate test by a significant reduction of paw-withdrawal latency from 242% to 99% above baseline. Using RT-PCR we demonstrated a down-regulation of mu-opioid receptor mRNA by 62% after morphine exposure (P < 0.05). After acute withdrawal of morphine from the mu-receptor by naloxone, the mu-opioid receptor mRNA levels in the dorsal root ganglia were restored to control levels within 24 h and the paw-withdrawal latency also returned to 280% above control. These data suggest that the peripheral nervous system may be an important site of opioid tolerance development.