The Naked Mole-Rat Has a Functional Purinergic Pain Pathway Despite Having a Non-Functional Peptidergic Pain Pathway

Naked mole-rats (Heterocephalus glaber) have adaptations within their pain pathway that are beneficial to survival in large colonies within poorly ventilated burrow systems, with lower O₂ and higher CO₂ ambient levels than ground-level environments. These adaptations ultimately lead to a partial disruption of the C-fiber pain pathway, which enables naked mole-rats to not feel pain from the acidosis associated with CO₂ accumulation. One hallmark of this disruption is that naked mole-rats do not express neuropeptides, such as Substance P and calcitonin gene-related peptide in their cutaneous C-fibers, effectively making the peptidergic pain pathway hypofunctional. One C-fiber pathway that remains unstudied in the naked mole-rat is the non-peptidergic, purinergic pathway, despite this being a key pathway for inflammatory pain. The current study aimed to establish the functionality of the purinergic pathway in naked mole-rats and the effectiveness of cannabinoids in attenuating pain through this pathway. Cannabinoids can manage chronic inflammatory pain in both humans and mouse models, and studies suggest a major downstream role for the purinergic receptor, P2X3, in this treatment. Here we used Ca²⁺-imaging of cultured dorsal root ganglion neurons and in vivo behavioral testing to demonstrate that the P2X3 pathway is functional in naked mole-rats. Additionally, formalin-induced inflammatory pain was reduced by the cannabinoid receptor agonist, WIN55 (inflammatory, but not acute phase) and the P2X3 receptor antagonist A-317491 (acute and inflammatory phases). This study establishes that the purinergic C-fiber pathway is present and functional in naked mole-rats and that cannabinoid-mediated analgesia occurs in this species.