Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice

Abstract

Although surgical trauma activates the anterior pituitary gland and elicits an increase in prolactin (PRL) serum levels that can modulate nociceptive responses, the role of PRL and the PRL-receptor (PRL-R) in thermal and mechanical hyperalgesia in postoperative pain is unknown. Acute postoperative pain condition was generated with the use of the hindpaw plantar incision model. Results showed endogenous PRL levels were significantly increased in serum, operated hindpaw and spinal cords of male and female rats 24 hours after incision. These alterations were especially pronounced in females. We then examined the role of the PRL system in thermal and mechanical hyperalgesia in male and female mice 3-168 hours after plantar incision with the use of knock-out (KO) mice with PRL or PRL-R gene ablations and in wild-type (WT) mice. WT mice showed postoperative cold hyperalgesia in a sex-dependent manner (only in females), but with no effect on heat hyperalgesia or mechanical allodynia in either sex. Studies in KO mice showed no effect of PRL and PRL-R gene ablation on heat and cold hyperalgesia in male mice, while heat hyperlgesia were reduced 3-72 hours post-surgery in female PRL and PRL-R KO mice. In contrast, PRL and PRL-R ablations significantly attenuated mechanical allodynia 3-72 hours post-surgery in both male and female mice. Overall, we found elevated PRL levels in serum, hindpaws and spinal cords after incision, and identify a contributory role for the PRL system in postoperative pain responses to thermal stimuli in females and to mechanical stimuli in both males and females.

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).…”

“…Because local trauma and inflammation lead to an increase in peripheral levels of PRL in female and to a lesser extent in male rats, it could be suggested that transient modulation of TRP channels by PRL in the periphery is one of underlying mechanisms for PRL-induced thermal (i.e. heat and cold) hyperalgesia (2)(3)(4). TRP channels are also involved in hypersensitivity to thermal and mechanical stimuli at presynaptic levels in the dorsal horn of the spinal cord and certain brain stem regions (62,63).…”

“…Western Blotting and pSTAT5 ELISA-Western blotting and ELISA were performed as described previously (3,21). Transfected CHO cells were homogenized by 20 strokes in a PotterElvehjem homogenizer in solution provided by ELISA kit (InstantOne ELISA for pSTAT5; eBioscience, San Diego, CA) and supplemented with protease inhibitors aprotinin (1 g/ml; Sigma-Aldrich), leupeptin (1 g/ml; Sigma-Aldrich), pepstatin (1 g/ml; Sigma-Aldrich), and phenylmethylsulfonyl fluoride (PMSF, 100 nM; Sigma-Aldrich).…”

“…Prolactin (PRL) 3 acts as an endocrine hormone, a growth factor, a neurotransmitter, and an immune modulator (1). 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).…”

“…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).…”