The glial cell's role in antinociceptive differential effects of oxytocin upon female and male rats

Background Sex plays a crucial role in pain processing and response to analgesic drugs. Indeed, spinal glia seems to be significant in the sexual dimorphism observed in the above effects. Recently, studies have associated oxytocin with antinociceptive effects, but these have been mainly performed in male animals; consequently, the influence of sex has been poorly explored. Methods: Using a model of spinal nociception that produces pain through activation of the spinal glia, that is, intrathecal (i.t.) lipopolysaccharide (LPS) injection, we analysed the changes in the analgesic response to i.t. oxytocin in female and male rats by behavioural (punctate mechanical hypersensitivity), electrophysiological (unitary extracellular recordings of wide dynamic range [WDR] cells) and molecular biology (real-time PCR of proinflammatory genes) experiments. Results We found that LPS-induced hypersensitivity was longer in female (>96 h) than in male (approximate to 4 h) rats. Besides, spinal oxytocin preferentially prevents the LPS-induced hypersensitivity in male rather than female rats. Indeed, LPS increases the spinal neuronal-evoked activity associated with the activation of peripheral A delta- and C-fibres and post-discharge in males, whereas only C-fibre discharge was enhanced in females. The electrophysiological data correlate with the fact that spinal oxytocin only prevented TNF-alpha and IL-1 beta synthesis in male rats. Conclusions Therefore, these data suggest that oxytocin-mediated analgesia depends on a sexual dimorphism involving activation of the spinal glia. These results reinforced the idea that different strategies are required to treat pain in men and women, and that oxytocin could be used preferentially to treat pain with a significant inflammatory component in men. Significance Statement Oxytocin is a molecule that emerges as a potent analgesic in preclinical and clinical studies. We investigated the contribution of glia to the response of oxytocin-induced analgesia and how sex influences in this response show that different strategies are required to treat pain in men and women, and that oxytocin could be used preferentially to treat pain with a significant inflammatory component in men.