Spinal Inhibition of P2XR or p38 Signaling Disrupts Hyperalgesic Priming in Male, but not Female, Mice

Paige, Candler; Maruthy, Gayathri Batchalli; Mejia, Galo L.; Dussor, Gregory; Price, Theodore J.

doi:10.1016/j.neuroscience.2018.06.012

Cited by 43 publications

(37 citation statements)

References 46 publications

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“…Strikingly, skepinone, a selective p38 inhibitor, not only attenuated CCI-induced mechanical allodynia exclusively in males, but also suppressed CCI-induced synaptic plasticity in males (Taves et al, 2016). Consistently, spinal inhibition of P2XR or p38 signaling was shown to disrupt hyperalgesic priming, a persistent pain condition induced by IL-6 and subsequent challenge with PGE2, in male but not female mice (Paige et al, 2018). Therefore, sex-specific p38 activation and signaling appears to be confined to the spinal cord in inflammatory and neuropathic pain conditions.…”

Section: Sex Dimorphism In Microglial Signaling In Painmentioning

confidence: 77%

Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

Chen

Zhang

Qadri

et al. 2018

Neuron

577

459

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The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions. We also reveal an emerging role of microglia in the resolution of pain, in part via specialized pro-resolving mediators including resolvins, protectins and maresins. We also discuss a possible role of microglia in chronic itch.

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Section: Sex Dimorphism In Microglial Signaling In Painmentioning

confidence: 77%

Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

Chen

Zhang

Qadri

et al. 2018

Neuron

577

459

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“…Together with the above examples, this suggests that even during early life, in male rodents use microglia in priming injury to produce persistent and latent pain states. It will be interesting to determine whether P2X4R signaling is also involved in neonatal incision pain priming, as it is involved in adult primed states (Paige et al, 2018) and in chronic pain conditions (Inoue, 2019).…”

Section: Generalizability Of Spinal Microglial-and/or P2x4r-dependencmentioning

confidence: 99%

Sex-Dependent Mechanisms of Chronic Pain: A Focus on Microglia and P2X4R

Halievski

Ghazisaeidi

Salter

2020

J Pharmacol Exp Ther

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For over two decades, purinergic signaling in microglia has persisted in the spotlight as a major pathomechanism of chronic pain. Of the many purinoreceptors, the P2X4R of the ionotropic family has a well-described causal role underlying chronic neuropathic pain. This review will first briefly examine microglial P2X4R signaling in the spinal cord as it relates to chronic pain through a historical lens, followed by a more in-depth examination of recent work, which has revealed major sex differences. We also discuss the generalizability of sex differences in microglial and P2X4R signaling in other pain conditions, as well as in non-spinal regions. Finally, we speculate on remaining gaps in the literature as well as what can be done to address them with the ultimate goal of using our collective knowledge to treat chronic pain effectively and in both sexes. Significance Statement. Effective treatments are lacking for chronic pain sufferers, and this may be explained by the vast sex differences underlying chronic pain mechanisms. In this Minireview, we focus on the roles of microglia and P2X4R in chronic pain, with specific attention to the circumstances under which these pathomechanisms differ between males and females. By delineating the ways in which pain occurs differently between the sexes, we can start developing successful therapies for all.

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“…Studies in both animals and humans demonstrate sexually dimorphic mechanisms controlling the development and resolution of chronic pain (Joseph et al, 2003; Sorge et al, 2015; Nasir et al, 2016; Taves et al, 2016; Lopes et al, 2017; Rosen et al, 2017; Mapplebeck et al, 2018; Paige et al, 2018; Dance, 2019; North et al, 2019; Patil et al, 2019b; Ray et al, 2019a; Rosen et al, 2019). Among these sex differences, several factors have been discovered that drive chronic pain specifically in males (Sorge et al, 2015; Taves et al, 2016; Mapplebeck et al, 2018; Megat et al, 2018; Paige et al, 2018; Shiers et al, 2018; Martin et al, 2019) but relatively little is known about such chronic pain mechanisms in females. There is evidence that these mechanisms are closely regulated by gonadal hormones (Traub and Ji, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Previous work indicates that sex-dependent mechanisms regulating hypersensitivity in inflammatory and neuropathic pain conditions can be attributed to distinct immune cell types: microglia in males (Sorge et al, 2011; Sorge et al, 2015; Taves et al, 2016; Paige et al, 2018) and T cells in females (Sorge et al, 2015). Importantly, there is an opinion that these cells are regulated by gonadal hormones.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study in rats demonstrated that hyperalgesic priming to carrageenan does not occur in females (Joseph et al, 2003). Subsequent studies in mice and rats have shown additional sexual dimorphisms (Megat et al, 2018; Paige et al, 2018; Inyang et al, 2019), across the lifespan (Moriarty et al, 2019), but none of them have observed a similar absence of priming in female rodents. In fact, our work shows, at least with IL-6 as the priming stimulus, that the magnitude and duration of the response to PGE 2 given peripherally or intrathecally is longer in female mice than male mice.…”

Section: Discussionmentioning

confidence: 99%

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Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Paige¹,

Barba-Escobedo

Mecklenburg

et al. 2020

Preprint

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Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.Significance StatementFemales are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice – where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

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Spinal Inhibition of P2XR or p38 Signaling Disrupts Hyperalgesic Priming in Male, but not Female, Mice

Cited by 43 publications

References 46 publications

Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

Sex-Dependent Mechanisms of Chronic Pain: A Focus on Microglia and P2X4R

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

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