Background Cannabigerol (CBG) is a non‐psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over‐the‐counter treatment for many forms of pain. However, there is very little research‐based evidence for the efficacy of CBG as an anti‐nociceptive agent. Methods To begin to fill this knowledge gap, we assessed the anti‐nociceptive effects of CBG in C57BL/6 mice using three different models of pain; cisplatin‐induced peripheral neuropathy, the formalin test, and the tail‐flick assay. Results Using the von Frey test, we found that CBG‐attenuated mechanical hypersensitivity evoked by cisplatin‐induced peripheral neuropathy in both male and female mice. Additionally, we observed that this CBG‐induced reduction in mechanical hypersensitivity was attenuated by the α2‐adrenergic receptor antagonist atipamezole (3 mg/kg, i.p.) and the CB1R antagonist, AM4113 (3 mg/kg, i.p.), and blocked by the CB2R antagonist/inverse agonist, SR144528 (10 mg/kg, i.p.). We found that the TRPV1 antagonist, SB705498 (20 mg/kg, i.p.) was unable to prevent CBG actions. Furthermore, we show that CBG:CBD oil (10 mg/kg, i.p.) was more effective than pure CBG (10 mg/kg) at reducing mechanical hypersensitivity in neuropathic mice. Lastly, we show that pure CBG and CBG:CBD oil were ineffective at reducing nociception in other models of pain, including the formalin and tail flick assays. Conclusions Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin‐induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain. Significance There are few effective treatments for neuropathic pain and neuropathic pain is projected to increase with the aging population. We demonstrate that CBG (cannabigerol) and CBG:CBD oil attenuate neuropathy‐induced mechanical hypersensitivity mice. Second, we identify receptor targets that mediate CBG‐induced reduction in mechanical hypersensitivity in neuropathic mice. Third, we demonstrate that an acute injection of CBG is anti‐nociceptive specifically for neuropathic pain rather than other forms of pain, including persistent pain and thermal pain.

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