Sexual dimorphism in vincristine-induced neuropathic pain, effect of prokineticin antagonism

Vincristine (VCR) use is often related to neuropathy and growing evidence suggest that several factors, including sex, may influence its development. We addressed VCR-induced neuropathic pain in male and female mice in relation to neuroinflammation and prokineticin (PK) system activation in the main stations involved in pain transmission: sciatic nerve, dorsal root ganglia and spinal cord. We also evaluated the efficacy of the PK system antagonist, PC1, in contrasting neuropathic pain, neuroinflammation and immune activation in both sexes. Female control mice were characterized by high basal levels of (neuro) inflammatory markers that do not influence their pain thresholds. VCR induced in male mice a more marked mechanical allodynia and thermal hyperalgesia in comparison to females, who were precociously sensitive to cold stimuli. Considering neuroinflammation, VCR male mice showed a marked up-regulation of the chemokine PK2 and its receptors, cytokines and glial markers in both PNS and CNS. Differently, in VCR female mice, neuroinflammation is attenuated moving from PNS towards the spinal cord, the least affected station by VCR treatment. Chronic treatment with PC1 promptly reduced mechanical and thermal hypersensitivity in male mice, while in females, PC1 had a delayed and lower effect. In addition, PC1 almost always counteracted neuroinflammation in male mice, but its effect is not always evident in females. In conclusion, our data describes a sexual dimorphism in the pathophysiology of VCR-induced neuropathic pain and a different effect of the PK antagonist in the two sexes, confirming the importance of conducting experiments in both sexes.