Cannabidiol (CBD) modulates the serotonin-kynurenine metabolic balance in the brain of morphine-tolerant neuropathic rats

Background: Neuropathic pain (NP) is a chronic and debilitating condition that remains difficult to treat, with opioids like morphine often leading to tolerance and reduced efficacy over time. Cannabidiol (CBD) has emerged as a potential therapeutic for NP even in morphine tolerance conditions; however, its effects on nociceptive modulation and neurotransmitter metabolism in morphine-tolerant NP models remain poorly understood. This study investigated the impact of CBD on mechanical hypersensitivity and on tryptophan (TRP) metabolism via the serotonin (5-HT) and kynurenine (KYN) pathways and dopamine (DA) in Wistar rats with NP and morphine tolerance. Methods: NP was induced using the spared nerve injury (SNI) model. Animals received morphine (5 mg/kg, subcutaneous (sc), twice daily) for 7 days to induce tolerance. On Day 8, rats were treated with CBD (20 mg/kg, ip) or vehicle. Mechanical hypersensitivity was assessed, and TRP metabolism and DA were evaluated in different brain regions and serum. Results: Repeated morphine induced tolerance to its analgesic effects. CBD significantly reduced mechanical hypersensitivity in non-tolerant rats, with a modest effect in morphine-tolerant animals. In tolerant rats, CBD increased 5-hydroxytryptophan (5-HTP)/TRP ratio in hippocampus and midbrain and reduced KYN levels in the hippocampus, indicating a shift toward 5-HT synthesis. CBD also lowered DA and the 5-HTP/TRP ratio in the brainstem, and decreased serum TRP and 5-HT. Conclusions: CBD treatment in NP morphine-tolerant rats exerted a modest effect on mechanical hypersensitivity and was associated with a partial counteraction of metabolic dysregulation by reducing KYN production and shifting TRP metabolism toward 5-HT synthesis (increased 5-HTP/TRP ratio). These findings suggest that CBD modulates 5-HT tone through region-specific mechanisms associated with the development of morphine tolerance.