Cannabigerol reverses mechanical allodynia in chemotherapy-induced peripheral neuropathy.

Cannabigerol reverses mechanical allodynia throughα-adrenergic modulation of thalamocortical signaling in chemotherapy-induced neuropathy.

Quinn W Wade, Nathan Morris, Diana E Sepulveda, Alonso Cortez-Resendiz, Christopher Brandl, Jennifer E Lausch, Mariya Starostina, Nicholas M Graziane

Br J Pharmacol

Dec 23, 2025

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Abstract

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and treatment-resistant side effect of platinum-based chemotherapy, characterised by mechanical allodynia. Cannabigerol (CBG), a non-psychoactive cannabinoid, has shown antinociceptive potential, but its site and mechanism of action remain unclear. We investigated whether CBG modulates thalamocortical circuitry to reverse mechanical allodynia in a mouse model of CIPN and whetherα-adrenoceptors (αARs) mediate these effects. EXPERIMENTAL APPROACH: C57BL/6 mice received weekly cisplatin injections to induce neuropathy. Mechanical sensitivity was assessed using von Frey testing. Chemogenetic and optogenetic tools were used to manipulate and monitor ventral posterolateral thalamus (VPL) to hindlimb region of the somatosensory cortex (S1HL) synapses. Whole-cell electrophysiology assessed synaptic properties ex vivo. CBG was administered systemically, locally and via bath application, with and without theα-adrenoceptor antagonist atipamezole orα-adrenoceptor shRNA knockdown in the VPL. KEY RESULTS: Cisplatin increased presynaptic neurotransmitter release at VPL-to-S1HL synapses, shown by a decrease in the paired-pulse ratio and reduced AMPA receptor variability. CBG reversed these changes and mechanical allodynia via a dose-dependent andα-adrenoceptor-dependent mechanism. Local and systemic CBG administration failed to reverse allodynia or synaptic changes in mice withα-adrenoceptor knockdown in the VPL. CBG had no effect on locomotor activity. CONCLUSIONS AND IMPLICATIONS: CBG reverses mechanical allodynia in CIPN by reducing presynaptic neurotransmission at VPL-to-S1HL synapses through the activation ofα-adrenoceptors. These findings identify a thalamocortical circuit mechanism and a cannabinoid-sensitive target for neuropathic pain treatment.