Cannabigerol reverses mechanical allodynia through α2A-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

doi:10.1111/bph.70281

Cannabigerol reverses mechanical allodynia through α_2A-adrenergic modulation of thalamocortical signaling in chemotherapy-induced neuropathy

Br J Pharmacol. 2025 Dec 23. doi: 10.1111/bph.70281. Online ahead of print.

Authors

Quinn W Wade¹, Nathan Morris^{1

2}, Diana E Sepulveda³, Alonso Cortez-Resendiz³, Christopher Brandl⁴, Jennifer E Lausch², Mariya Starostina⁵, Nicholas M Graziane⁶

Affiliations

¹ Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA.
² Biomedical Sciences Graduate Program, Penn State College of Medicine, Hershey, Pennsylvania, USA.
³ Department of Neuroscience and Experimental Therapeutics, Penn State College of Medicine, Hershey, Pennsylvania, USA.
⁴ Anatomy Graduate Program, Penn State College of Medicine, Hershey, Pennsylvania, USA.
⁵ Doctor of Medicine Program, Penn State College of Medicine, Hershey, Pennsylvania, USA.
⁶ Departments of Anesthesiology and Perioperative Medicine and Neuroscience and Experimental Therapeutics, Penn State College of Medicine, Hershey, Pennsylvania, USA.

PMID: 41435878
DOI: 10.1111/bph.70281

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 whether α_2A-adrenoceptors (α_2AARs) 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.

Keywords: cannabigerol (CBG); chemotherapy‐induced peripheral neuropathy (CIPN); cisplatin; mechanical allodynia; optogenetics; paired‐pulse ratio (PPR); presynaptic neurotransmission; somatosensory cortex (S1HL); thalamocortical circuit; ventral posterolateral thalamus (VPL); whole‐cell electrophysiology; α2A‐adrenergic receptor (α2AAR).

Abstract

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