Cannabigerol reverses mechanical allodynia through α 2A ‐adrenergic modulation of thalamocortical signaling in chemotherapy‐induced neuropathy

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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 whether α 2A ‐adrenoceptors (α 2A ARs) 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 the α 2A ‐adrenoceptor antagonist atipamezole or α 2A ‐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 and α 2A ‐adrenoceptor‐dependent mechanism. Local and systemic CBG administration failed to reverse allodynia or synaptic changes in mice with α 2A ‐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 of α 2A ‐adrenoceptors. These findings identify a thalamocortical circuit mechanism and a cannabinoid‐sensitive target for neuropathic pain treatment.