Papers of the Week

Although tolerance serves as a major limitation in the long-term clinical use of opioids in patients with chronic severe pain, mechanisms of opioid tolerance are poorly understood. In this study, a morphine tolerance model was established by subcutaneously injecting male rats with morphine (10 mg/kg) twice a day for 10 consecutive days. In addition, a subset of morphine-tolerant rats underwent testosterone replacement therapy. The levels of mu-opioid receptor (MOR) mRNA and protein in the trigeminal ganglia (TGs) of morphine-tolerant versus control rats and of morphine-tolerant rats with vs. without testosterone replacement therapy were measured. We found that testosterone levels were significantly lower in morphine-tolerant rats than in the controls (1.248 ± 0.231 ng/ml vs. 2.223 ± 0.153 ng/ ml, respectively; p =  0.008). Furthermore, chronic morphine exposure led to a downregulation in the levels of MOR mRNA to 79.3%, and of MOR protein to 68.9%. Testosterone replacement therapy restored MOR mRNA and protein levels specifically in rats who had developed a tolerance to morphine, thereby suggesting a potential role of testosterone in the opioid-receptor response to chronic morphine exposure. In summary, our study provides evidence for the involvement of testosterone in the proper regulation of the peripheral MOR system in rats following prolonged morphine exposure. We also suggest that analgesic therapeutic measures should take into account the testosterone levels of patients who have built up a tolerance to morphine.