Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

Abstract

Patil MJ, Ruparel SB, Henry MA, Akopian AN. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain. Am J Physiol Endocrinol Metab 305: E1154-E1164, 2013. First published September 10, 2013; doi:10.1152/ajpendo.00187.2013 is a hormone produced in the anterior pituitary but also synthesized extrapituitary where it can influence diverse cellular processes, including inflammatory responses. Females experience greater pain in certain inflammatory conditions, but the contribution of the PRL system to sexdependent inflammatory pain is unknown. We found that PRL regulates transient receptor potential (TRP) channels in a sex-dependent manner in sensory neurons. At Ͼ20 ng/ml, PRL sensitizes TRPV1 in female, but not male, neurons. This effect is mediated by PRL receptor (PRL-R). Likewise, TRPA1 and TRPM8 were sensitized by 100 ng/ml PRL only in female neurons. We showed that complete Freund adjuvant (CFA) upregulated PRL levels in the inflamed paw of both male and female rats, but levels were higher in females. In contrast, CFA did not change mRNA levels of long and short PRL-R in the dorsal root ganglion or spinal cord. Analysis of PRL and PRL-R knockout (KO) mice demonstrated that basal responses to cold stimuli were only altered in females, and with no significant effects on heat and mechanical responses in both sexes. CFA-induced heat and cold hyperalgesia were not changed in PRL and PRL-R KO compared with wild-type (WT) males, whereas significant reduction of heat and cold post-CFA hyperalgesia was detected in PRL and PRL-R KO females. Attenuation of CFA-induced mechanical allodynia was observed in both PRL and PRL-R KO females and males. Thermal hyperalgesia in PRL KO females was restored by administration of PRL into hindpaws. Overall, we demonstrate a sex-dependent regulation of peripheral inflammatory hyperalgesia by the PRL system. prolactin receptor; transient receptor potential V1; transient receptor potential A1; transient receptor potential M8; female; inflammation; pain MANY HUMAN CHRONIC INFLAMMATORY conditions are associated with hyperprolactinemia, and this increase in prolactin (PRL) levels can lead to serious health issues related to cancer, infertility, inflammatory diseases, and body weight (11,42,48,73). Human inflammatory conditions with increased PRL serum levels include the severe form of progressive systemic sclerosis (34, 69), the active phase of systemic lupus erythematosus (37, 74), rheumatoid arthritis (44), polymyalgia rheumatica (68), and autoimmune thyroid diseases (26). Unlike chronic inflammation, acute inflammation in animals triggers an accumulation of endogenous PRL at the site of inflammation, but not in blood serum (64). Altogether, these findings suggest that acute inflammation upregulates PRL via extrapituitary mechanisms, whereas chronic inflammation induces PRL via both pituitary and extrapituitary pathways (64, 75).Elevated PRL can have modulatory effects on metabolic/ endocrine and the ...

Mechanisms of Transient Signaling via Short and Long Prolactin Receptor Isoforms in Female and Male Sensory Neurons

“…PRL can modulate the function of CNS and PNS neurons, and it plays a critical role in diverse bodily functions such as maternal behavior (48), appetite (49), sexual receptivity (50), and hypersensitivity to painful stimuli (2)(3)(4), where the action of PRL on neurons can be either acute/transient or long term. Transient effects of PRL have been characterized in many neuronal types including gonadotropin-releasing hormone neurons, tuberoinfundibular dopamine neurons, the anteroventralperiventricular nucleus, and dorsal root ganglion and TG sensory neurons (2,7,17,51,52).…”

“…Transient effects of PRL have been characterized in many neuronal types including gonadotropin-releasing hormone neurons, tuberoinfundibular dopamine neurons, the anteroventralperiventricular nucleus, and dorsal root ganglion and TG sensory neurons (2,7,17,51,52). Even though it is well known that long term effects of PRL are mainly mediated via the JAK/STAT pathways controlling gene expression modulation (15,43), the molecular mechanisms underlying the transient effect of PRL in neurons are not known.…”

“…PRL is produced by the anterior pituitary gland and in other tissues (extrapituitary PRL) in a variety of pain conditions (2)(3)(4)(5)(6). The release of PRL from both the pituitary and extrapituitary tissues is sex-dependent and correlates with estrogen levels in serum (2,4,7). The systemic and local release of PRL can modulate the activity of a wide variety of cell types, including peripheral sensory neurons in pain conditions where this modulation contributes to hyperalgesic responses (2-4, 8, 9).…”

“…The systemic and local release of PRL can modulate the activity of a wide variety of cell types, including peripheral sensory neurons in pain conditions where this modulation contributes to hyperalgesic responses (2-4, 8, 9). Even though the molecular mechanisms responsible for PRL-directed modulation of nociception are unknown, one possible mechanism is the PRL regulation of sensory neuronal channels, including transient receptor potential (TRP) channels that play critical roles in hyperalgesia/pain (2,7,10,11). Because PRL can differentially activate nociceptors in a sex-dependent manner (2), this modulation may involve short lasting (transient) effects that could vary in males compared with females.…”

“…Even though the molecular mechanisms responsible for PRL-directed modulation of nociception are unknown, one possible mechanism is the PRL regulation of sensory neuronal channels, including transient receptor potential (TRP) channels that play critical roles in hyperalgesia/pain (2,7,10,11). Because PRL can differentially activate nociceptors in a sex-dependent manner (2), this modulation may involve short lasting (transient) effects that could vary in males compared with females. Accordingly, one of the main goals of this study is to define mechanisms underlying transient effects of PRL in female and male sensory neurons because this transient modulation by PRL may represent an important mechanism that contributes to analgesia and pain.…”