Problem statement: The present study was performed to determine the effect of Intracerebroventricular (ICV) administration of W-7, a specific calmodulin inhibitor, on the analgesic effect and development of tolerance to antinociceptive effect of acute and chronic morphine administration respectively. Approach: This study was carried out on male wistar rats, weighing 200-250 g. For acute experimental protocol, Morphine was injected intraperitonealy in a single dose (5 mg kg −1 ). For chronic

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... rimental protocol, Morphine was administered daily (15 mg kg −1 for 8 days). The threshold to thermal nociceptive stimuli was measured by tail-flick test. In acute and chronic experiments, W-7 (0.25, 0.5 and 1 µmol/rat) was injected through ICV at different paradigms. Maximal Possible Effect percentage (MPE%) was considered as analgesia index. Results: Our result showed that W-7 (0.25, 0.5 and 1 µmol/rat) injections before acute morphine administration significantly reduced the analgesic effect of morphine compared with morphine treated group (all p<0.05). Chronic morphine exposure induced tolerance to its antinociceptive effect and administration of W-7 (0.5 and 1 µmol/rat) decreased the development of tolerance to it. Conclusion: In conclusion these data showed that acute administration of W-7 reduced the analgesics effect of morphine and chronic injection of W-7 inhibited the development of morphine tolerance which indicates that calmodulin and its dependent pathways may play a role in the morphine tolerance processes.