Potential effects of cannabidiol on formalin-induced inflammatory pain in morphine-dependent rats

Chronic morphine exposure leads to tolerance and dependence, complicating pain management and reducing the efficacy of opioid analgesics. Cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, has been recognized for its anti-inflammatory and analgesic potential. This study examined the effects of CBD on acute and inflammatory phases of formalin-induced nociception in morphine-dependent and non-dependent rats. Eighty-four male Wistar rats were divided into the control (non-dependent) and dependent groups. Morphine dependence was induced through an oral escalating-dose regimen in drinking water containing 3% sucrose (to mask bitterness) for 14 days, while controls received only sucrose. CBD (25-200μg/5 μL, ICV) was administered prior to the formalin test. Formalin injection produced a clear biphasic nociceptive response (P < 0.001 in both phases), confirming the model's validity. Morphine dependence alone did not significantly affect baseline pain responses (P > 0.05). However, CBD produced a significant, dose-dependent reduction in pain behaviors during both the early (0-5 min) and the late (20-50 min) phases (P<0.001 vs. vehicle). The 100 μg/5 μL and 200 μg/5 μL doses showed the most robust and consistent antinociceptive effect. CBD produced robust antinociceptive effects in both morphine-treated and non-treated rats, with no statistically significant difference between groups. Open-field results indicated no significant differences in locomotor activity, confirming that the observed analgesia was not related to motor impairment. These findings demonstrate that CBD effectively attenuates both acute and inflammatory pain. Moreover, it maintains its effectiveness in animals treated with morphine. This highlights its potential as a non-opioid supplementary therapy for managing pain in individuals with opioid dependence.