Recent studies have demonstrated sexual dimorphisms in the mechanisms contributing to the development of chronic pain. Here we tested the hypothesis that microglia might preferentially regulate hyperalgesic priming in male mice. We based this hypothesis on evidence that microglia preferentially contribute to neuropathic pain in male mice via ionotropic purinergic receptor (P2XR) or p38 mitogen-activated protein kinase (p38) signaling. Mice given a single-priming injection of the soluble human interleukin-6 receptor (IL-6r) and then a second injection of prostaglandin E2 (PGE), which unmasks hyperalgesic priming, shows a significant increase in levels of activated microglia at 3 h following the PGE injection in both male and female mice. There was no change in microglia following PGE. Intrathecal injection of the P2X3/4 inhibitor TNP-ATP blocked the initial response to IL-6r in both males and females, but only blocked hyperalgesic priming in male mice. Intrathecally applied p38 inhibitor, skepinone, had no effect on the initial response to IL-6r but attenuated hyperalgesic priming in males only. Neither TNP-ATP nor skepinone could reverse priming once it had already been established in male mice suggesting that these pathways must be inhibited early in the development of hyperalgesic priming to have an effect. Our work is consistent with previous findings that P2XR and p38 inhibition can lead to male-specific effects on pain behaviors in mice. However, given that we did not observe microglial activation at time points where these drugs were effective, our work also questions whether these effects can be completely attributed to microglia.

Background: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. Objective: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. Methods: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. Results: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects’ reaction time and predicted reaction time after controlling for disease processes. Conclusion: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS.

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