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

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. 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. 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. 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.