Sex-dependent analgesic effects of phoenixin-14 on mechanical allodynia in mouse models of neuropathic and inflammatory pain

Chronic pain is a common complication of many diseases, often leading to severe hyperalgesia and allodynia with limited therapeutic options. Opioids are restricted in widespread clinical use due to side effects such as addiction and tolerance. Therefore, identifying novel pain-modulating targets is of great significance for the comprehensive and long-term treatment of chronic pain. This study reports that an endogenous polypeptide, phoenixin-14 (PNX-14), exhibits sexually dimorphic regulatory effects in various pain models. Briefly, intrathecally administered PNX-14 produces a more potent, dose-dependent elevation of pain thresholds in female mice than in male mice under physiological conditions. In models of spared nerve injury-induced neuropathic pain and complete Freund's adjuvant-induced inflammatory pain, intrathecal injection of PNX-14 elicited antinociceptive responses in both sexes, yet the magnitude observed in females was significantly greater than that in males. Further investigation revealed that this sexually dimorphic effect is not attributable to differential pharmacokinetics, as the plasma half-life of PNX-14 shows no difference between male and female mice both in vivo and in vitro. Notably, surgical and pharmacological manipulations revealed that PNX-14-regulated pain is promoted by estrogen but suppressed by androgen, suggesting an involvement of sex hormones. These results collectively position PNX-14 as a novel, nonopioid, and female-specific target for chronic pain management.