The Effects of W7, a Specific Calmodulin Inhibitor, to the Antinociceptive Effects of Morphine in Adrenalectomized Rats

Problem statement: This study was performed to evaluate the effect of W7 (specific calmodulin inhibitor) on morphine induced analgesia in Adrenalectomized (ADX) rats by tail-flick test. Approach: Tolerance to morphine was induced in male Wistar rats by daily injections of morphine (15 mg kg^-1, i.p) for 8 days. Adrenalectomy was performed under general anesthesia with intraperitoneal (i.p) injection of ketamine (50 mg kg^-1) and xylazine (5 mg kg^-1). In sham operated animals only the incision was made but adrenals were not removed. Five days after surgery, W7 (0.25, 0.5, 1 and 2 μmol rat^-1) was injected Intracerebroventricularlly (ICV) concomitant with morphine (15 mg kg^-1, i.p) for 8 consecutive days. Tail Flick Latency (TFL) was used to assess the nociceptive response at days 1, 3, 5 and 8 before and 30 min after morphine administration in sham operated and ADX rats. Maximal Possible Effect percentage (MPE %) was considered as analgesia index. Results: The results showed that daily morphine injection caused a marked analgesia in rats, but MPE % decreased significantly after 8 days which shows the development of tolerance to morphine (p<0.05). MPE % following morphine treatment in ADX rats was significantly greater than sham operated rats (p<0.05) and W7 (0.5, 1 and 2 micromol/rat/ICV) significantly attenuated the development of tolerance to morphine in ADX rats compared to sham operated rats (p<0.05 and p<0.001). Corticosterone replacement reversed the effect of W7 on ADX rats (p<0.005). Conclusion: The results of this study showed that hypothalamic- pituitary-adrenal axis and calmodulin may play a role in the development of tolerance to morphine antinociceptive effects in rats.