The purpose of this study was to evaluate the participation of spinal peroxisome proliferator-activated receptor gamma (PPARγ) in the antiallodynic effect of cannabidiol, the expression of PPARγ in sites relevant to the spinal nociceptive processing, and the effect of this cannabinoid on cognitive deficits induced by neuropathic pain in female mice. Either acute or repeated treatment with cannabidiol reduced tactile allodynia and spontaneous pain (flinching) in female neuropathic mice. Pioglitazone partially reduced tactile allodynia, and this effect was fully blocked by the PPARγ antagonist GW9662.

Likewise, intrathecal injection of cannabidiol reduced tactile allodynia, while PPARγ antagonist GW9662 or 5-HT_1A receptor antagonist WAY-100635, but not the PPARα antagonist GW6479, partially prevented this effect. GW9662 and WAY-100635 administrated per se did not modify tactile allodynia in neuropathic female mice. Co-administration of GW9662 and WAY-100635 fully prevented the antiallodynic effect of cannabidiol in mice. Nerve injury up-regulated PPARγ expression at the spinal cord and dorsal root ganglia, while cannabidiol further enhanced nerve injury-induced up-regulation of PPARγ expression in both tissues. Repeated intrathecal injection of cannabidiol reduced tactile allodynia and several pain makers (ERK, p-ERK, p38MAPK and p-p38MAPK). In addition, this treatment restored nerve injury-induced interleukin-10 down-regulation and increased PPARγ expression at the spinal cord.

Repeated treatment with cannabidiol also improved nerve injury-induced cognitive impairment in mice. These results provide compelling evidence for the involvement of PPARγ in the antiallodynic effect of cannabidiol in mice and highlight its multifaceted therapeutic potential in neuropathic pain management and its comorbidities. PERSPECTIVE: The present study reveals cannabidiol’s dual effects in female mice by reducing neuropathic pain through spinal PPARγ and 5-HT_1A receptor activation and ameliorating nerve injury-induced cognitive impairment. These findings may assist clinicians seeking new therapeutic approaches for managing neuropathic pain and its associated cognitive deficits.