Abstract
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.