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, i.p) for 8 days. Adrenalectomy was performed under general anesthesia with intraperitoneal (i.p) injection of ketamine (50 mg kg) and xylazine (5 mg kg). 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) was injected Intracerebroventricularlly (ICV) concomitant with morphine (15 mg kg, 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 hypothalamicpituitary-adrenal axis and calmodulin may play a role in the development of tolerance to morphine antinociceptive effects in rats.