Neuroendocrine Mechanisms Governing Sex Differences in Hyperalgesic Priming Involve Prolactin Receptor Sensory Neuron Signaling

Paige, Candler; Barba-Escobedo, Priscilla A.; Mecklenburg, Jennifer; Patil, Mayur; Goffin, Vincent; Grattan, David R.; Dussor, Gregory; Akopian, Armen N.; Price, Theodore J.

doi:10.1523/jneurosci.1499-20.2020

Cited by 47 publications

(50 citation statements)

References 82 publications

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“…Our findings support the conclusion that CGRP promotes mechanical sensitization in the DRG/spinal cord system, but primarily in female rodents. This adds to a growing body of evidence identifying signaling pathways that promote pain specifically in female animals in numerous models of chronic pain (Patil et al, 2013; Sorge et al, 2015; Avona et al, 2019; Patil et al, 2019b; Patil et al, 2019a; Paige et al, 2020; Avona et al, 2021). We found that CGRP, acting both in the periphery and CNS regulates early pain signaling in female mice and rats but that more persistent effects, such as those involved in the maintenance of hyperalgesic priming, require CNS CGRP signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In females, depletion of microglia does not reverse nerve injury-induced hypersensitivity and it appears that Tcells may play a critical role in promoting chronic pain (Sorge et al, 2015), although there is also evidence that T-cells promote pain resolution in both sexes (Krukowski et al, 2016;Laumet et al, 2019). Another female-specific pain promoting mechanism is prolactin signaling, which sensitizes female nociceptors through a direct action on the prolactin receptor (Patil et al, 2013;Patil et al, 2019b;Paige et al, 2020). Two mechanisms could underlie this sex difference in responses to prolactin, a sexually dimorphic expression pattern for the prolactin receptor in subtypes of dorsal root ganglia (DRG) neurons (Patil et al, 2019a), and/or a female-specific translation of the prolactin receptor at central and peripheral terminals of nociceptors (Patil et al, 2019b;Paige et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Another female-specific pain promoting mechanism is prolactin signaling, which sensitizes female nociceptors through a direct action on the prolactin receptor (Patil et al, 2013;Patil et al, 2019b;Paige et al, 2020). Two mechanisms could underlie this sex difference in responses to prolactin, a sexually dimorphic expression pattern for the prolactin receptor in subtypes of dorsal root ganglia (DRG) neurons (Patil et al, 2019a), and/or a female-specific translation of the prolactin receptor at central and peripheral terminals of nociceptors (Patil et al, 2019b;Paige et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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A female-specific role for Calcitonin Gene-Related Peptide (CGRP) in rodent pain models

Paige

Plasencia-Fernandez²,

Kume

et al. 2021

Preprint

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We aimed to investigate a potentially sexually dimorphic role of Calcitonin Gene-Related Peptide (CGRP) in mouse and rat models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 (IL-6) signaling, CGRP receptor antagonists, olcegepant and CGRP8-37, both given intrathecally, blocked and reversed hyperalgesic priming only in females. A monoclonal antibody against CGRP, given systemically, blocked priming specifically in female rodents but failed to reverse it. In the spared nerve injury (SNI) model, there was a transient effect of both CGRP antagonists, given intrathecally, on mechanical hypersensitivity in female mice only. Consistent with these findings, intrathecally applied CGRP caused a long-lasting, dose-dependent mechanical hypersensitivity in female mice but more transient effects in males. This CGRP-induced mechanical hypersensitivity was reversed by the KCC2 activator, CLP257 suggesting a role for anionic plasticity in the dorsal horn in the pain-promoting effects of CGRP in females. In spinal dorsal horn slices, CGRP shifted GABAA reversal potentials to significantly more positive values but, again, only in female mice. Therefore, CGRP may regulate KCC2 expression and/or activity specifically in females. However, KCC2 hypofunction promotes mechanical pain hypersensitivity in both sexes because CLP257 alleviated hyperalgesic priming in male and female mice. We conclude that CGRP promotes pain plasticity in female mice, but has a limited impact in male mice. Significance Statement: The majority of patients impacted by chronic pain are women. Mechanistic studies in rodents are creating a clear picture that molecular events promoting chronic pain are different in male and female animals. Far more is known about chronic pain mechanisms in male animals. We sought to build on recent evidence showing that CGRP is a more potent and efficacious promoter of headache pain in female than in male rodents. To test this, we used hyperalgesic priming and the spared nerve injury (SNI) neuropathic pain models in mice. Our findings show a clear sex dimorphism wherein CGRP promotes pain in female but not male mice. Our work suggests that CGRP antagonists could be tested for efficacy in women for a broader variety of pain conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A female-specific role for Calcitonin Gene-Related Peptide (CGRP) in rodent pain models

Paige

Plasencia-Fernandez²,

Kume

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In these animals, higher grimace scores were also recorded. In female mice, already sensitized, for example, by opioids [ 39 ] or the inflammatory agent IL-6 [ 16 ], even lower doses of prolactin could elicit a profound pain response. In search for identification of interaction between sex hormones and prolactin, behavioral tests have also shown that administration of prolactin can induce acute nociception in intact females but not in ovariectomized rats [ 38 ].…”

Section: Prolactin and Migraine: Basic Researchmentioning

confidence: 99%

“…Interestingly, hypersensitivity levels of stressed animals that received bromocriptine returned to baseline faster. Studies have also found that knockout of the prolactin receptor from Nav1.8-expressing nociceptors did not affect males but reduced the priming response to nitric oxide donors after stress in knockout females [ 8 , 16 , 78 ]. Recent data in mice have indicated that different stressors, such as surgery and inflammation, could elevate prolactin levels [ 77 , 79 ] predominantly in females.…”

Section: Prolactin and Migraine: Basic Researchmentioning

confidence: 99%

A Link Between Migraine and Prolactin: the Way Forward

Gazerani

2021

Future Sci. OA

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Migraine is an incapacitating neurological disorder that predominantly affects women. Sex and other hormones (e.g., oxytocin, and prolactin) may play a role in sexual dimorphic features of migraine. Initially, prolactin was recognized for its modulatory action in milk production and secretion; later, its roles in the regulation of the endocrine, immune and nervous systems were discovered. Higher prolactin levels in individuals with migraine were found in earlier studies, with a female sex-dominant trend. Studies that are more recent have identified that the expression of prolactin receptor in response to neuronal excitability and stress depends on sex with a dominant role in females. These findings have opened up potentials for explanation of sex-related pathophysiology of migraine, but have left some unanswered questions. This focused review examines the past and present of the link between prolactin and migraine, and presents open questions and directions for future experimental and clinical efforts.

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Characterization of Fragile X Mental Retardation Protein expression in human nociceptors and their axonal projections to the spinal dorsal horn

Mitchell

Cook

Shiers

et al. 2023

J of Comparative Neurology

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Fragile X Mental Retardation Protein (FMRP) regulates activity‐dependent RNA localization and local translation to modulate synaptic plasticity throughout the central nervous system. Mutations in the FMR1 gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS premutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated dorsal root ganglion (DRG) neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation‐dependent nociceptive sensitization. Activity‐dependent, local translation is a key mechanism for enhancing primary nociceptor excitability that promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human DRG and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane‐associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene‐related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain.

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Neuroendocrine Mechanisms Governing Sex Differences in Hyperalgesic Priming Involve Prolactin Receptor Sensory Neuron Signaling

Abstract: Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling Abbreviated Title: Prolactin promotes chronic pain in females

Cited by 47 publications

References 82 publications

A female-specific role for Calcitonin Gene-Related Peptide (CGRP) in rodent pain models

A female-specific role for Calcitonin Gene-Related Peptide (CGRP) in rodent pain models

A Link Between Migraine and Prolactin: the Way Forward

Characterization of Fragile X Mental Retardation Protein expression in human nociceptors and their axonal projections to the spinal dorsal horn

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