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

Abstract

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 (≈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 Aδ-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-α and IL-1β 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.

Up‐regulation of oxytocin receptors on peripheral sensory neurons mediates analgesia in chemotherapy‐induced neuropathic pain

“…In this study, OXT was administrated intravenously and only exhibited antinociceptive effects in PTX‐treated mice. We did not find sexual dimorphism in this study, even though it was reported that the antinociceptive effects of OXT exhibit a sex difference in either lipopolysaccharide (LPS)‐ or carrageenan‐induced pain models (Chow et al, 2016; Salinas‐Abarca et al, 2022). It should be noted that the effects of OXT were observed over a short time after LPS or carrageenan treatment, and the difference may be due to the activation of spinal glia or a higher expression of insulin‐regulated aminopeptidase (IRAP) in the spinal cord of female rats.…”

Stomatin-like protein 3 modulates the responses of Aδ, but not C fiber bone afferent neurons to noxious mechanical stimulation in an animal model of acute experimental bone pain

“…Area under the curve (AUC) was determined using the trapezoid rule between 0 and 30 min for individual animals to determine the overall effect of each treatment between timepoints on pain behaviour. 29 For analyses of the differences in AUC, a One-way ANOVA followed by Dunnett’s post hoc analysis was used to compare treatment groups. Post hoc analyses were performed only if the ANOVA reported significant effects.…”

“…28 Here we used a dynamic weightbearing apparatus to confirm freely moving animals also have increased pain behaviour in response to intra-osseous application of carrageenan, and to determine whether inhibition of STOML3 oligomerisation with OB-1 can attenuate that pain behaviour. Two-way ANOVA with repeated measures revealed a significant treatment effect for time spent on injected limb (Figure 3a and c [2.165], DFn [2], DFd [29], p = 0.022) and total weight-bearing on the injected limb (Figure 3b and d [7.937] DFn [2], DFd [28], p = 0.022). Post-hoc testing revealed that animals treated with carrageenan + saline spent significantly less time on the injected limb at 15 and 30 min (Dunnett's p < 0.05), and had significantly reduced weight-bearing on the injected limb at 15 and 30 min (Dunnett's p < 0.05), in comparison to animals treated with saline alone.…”