Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex‐dependent

Patil, Mayur; Hovhannisyan, Anahit H.; Wangzhou, Andi; Mecklenburg, Jennifer; Koek, Wouter; Goffin, Vincent; Grattan, David R.; Boehm, Ulrich; Dussor, Gregory; Price, Theodore J.; Akopian, Armen N.

doi:10.1111/jne.12759

Cited by 38 publications

(37 citation statements)

References 45 publications

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“…Prlr is expressed not only in sensory neurons but also in DRG fibroblasts and satellite glial cells, some immune cells, and possibly by intrinsic spinal cord neurons (Ben-Jonathan et al., 2008, Haring et al., 2018, Patil et al., 2014, Patil et al., 2019). Here, we evaluated whether sensory neuronal Prlr is essential in female-selective regulation of chemical-induced, inflammatory, and neuropathic pain.…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that Prlr mRNA should have predominant expression in female compared with male sensory neurons. Prlr mRNA is mainly expressed in a subset of medium- and small-sized peptidergic and CGRP − /trpV1 + sensory neurons of female and male mice (Patil et al., 2019). Prlr + medium-sized peptidergic neurons can be divided into two subpopulations: NPY2R + and NPY2R − (Patil et al., 2019).…”

Section: Resultsmentioning

confidence: 99%

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Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism

et al. 2019

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SummaryMany clinical and preclinical studies report an increased prevalence and severity of chronic pain among females. Here, we identify a sex-hormone-controlled target and mechanism that regulates dimorphic pain responses. Prolactin (PRL), which is involved in many physiologic functions, induces female-specific hyperalgesia. A PRL receptor (Prlr) antagonist in the hind paw or spinal cord substantially reduced hyperalgesia in inflammatory models. This effect was mimicked by sensory neuronal ablation of Prlr. Although Prlr mRNA is expressed equally in female and male peptidergic nociceptors and central terminals, Prlr protein was found only in females and PRL-induced excitability was detected only in female DRG neurons. PRL-induced excitability was reproduced in male Prlr+ neurons after prolonged treatment with estradiol but was prevented with addition of a translation inhibitor. We propose a novel mechanism for female-selective regulation of pain responses, which is mediated by Prlr signaling in sensory neurons via sex-dependent control of Prlr mRNA translation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism

et al. 2019

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“…Responsiveness to PRL in sensory neurons is substantially higher in females (>40 fold) than in males (Patil et al, 2013b; Patil et al, 2019b; Patil et al, 2019a), and strictly controlled by E-2 (Diogenes et al, 2006; Patil et al, 2019b). Endogenous and extra-pituitary PRL is elevated in paw and spinal cord after inflammation and surgical injury (Scotland et al, 2011; Patil et al, 2013a).…”

Section: Resultsmentioning

confidence: 99%

“…The neuroendocrine hormone PRL and its receptor Prlr fit all these requirements. First, Prlr-mediated PRL effects are sex- and gonadal hormone-dependent in many tissues and cell types, including sensory neurons (Torner et al, 2001; Ben-Jonathan et al, 2008; Belugin et al, 2013; Patil et al, 2013a; Patil et al, 2019b; Patil et al, 2019a). Second, many clinical and preclinical studies show that endogenous release of PRL from both pituitary and extra-pituitary origins is induced by inflammation and tissue injury (Chernow et al, 1987; Noreng et al, 1987; BenJonathan et al, 1996; Yardeni et al, 2007; Scotland et al, 2011; Patil et al, 2013a).…”

Section: Discussionmentioning

confidence: 99%

“…Prolactin (PRL) and its receptor (Prlr) are prime candidates for this potential mechanism, since responsiveness to PRL in a variety of cells, including sensory neurons, is closely regulated by estrogen (Childs et al, 1999; Pi and Voogt, 2002; Diogenes et al, 2006; Belugin et al, 2013). Thus, Prlr signaling sensitizes pain-related ion channels and causes increased excitability in nociceptors specifically in females (Diogenes et al, 2006; Patil et al, 2013b; Liu et al, 2016; Patil et al, 2019b; Patil et al, 2019a). Moreover, Prlr function in female nociceptors is governed by estrogen signaling via a non-genomic pathway that involves sex-specific translation of Prlr mRNA (Patil et al, 2019b).…”

Section: Introductionmentioning

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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Meningeal CGRP‐Prolactin Interaction Evokes Female‐Specific Migraine Behavior

Avona

Mason

Burgos-Vega

et al. 2021

Annals of Neurology

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Objective Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female‐specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges. Methods Prolactin, CGRP, and receptor antagonists CGRP8‐37 or Δ1‐9‐G129R‐hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back‐labeled trigeminal ganglia (TG) neurons was used to assess PRL‐induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured. Results We found that dural PRL produced sustained and long‐lasting migraine‐like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little‐to‐no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8‐37 decreases migraine‐like responses to dural PRL. Reciprocally, Δ1‐9‐G129R‐hPRL attenuates dural CGRP‐induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine‐like responses to dural CGRP. Interpretation This CGRP‐PRL interaction in the meninges is a mechanism by which these peptides could produce female‐selective responses and increase the prevalence of migraine in women. ANN NEUROL 2021;89:1129–1144

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Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex‐dependent

Cited by 38 publications

References 45 publications

Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism

Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism

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

Meningeal CGRP‐Prolactin Interaction Evokes Female‐Specific Migraine Behavior

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