Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia

Abstract

Prolactin (PRL) is a hormone and a neuromodulator. PRL sensitizes TRPV1 responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-dependent manner. To address these questions, we examined inflammation-induced release of endogenous PRL, and its regulation of thermal hyperalgesia in female and male rats. PRL is expressed in several types of peripheral neuronal and non-neuronal cells, including TRPV1-positive nerve fibers, preadipocytes and activated macrophages/monocytes localized in the vicinity of nerves. Evaluation of PRL levels in hindpaws and plasma indicated that complete Freund’s adjuvant (CFA) stimulates release of peripheral, but not systemic PRL within 6–48h in both ovariectomized females with estradiol replacement (OVX-E) and male rats. The time course of release varies in OVX-E and male rats. We next employed the prolactin receptor (PRL-R) antagonist, Δ1-9-G129R-hPRL to assess the role of locally-produced PRL in nociception. Applied at a ratio of 1:1 (PRL:Δ1-9-G129R-hPRL; 40nM each), this antagonist was able to nearly (≈80%) reverse PRL-induced sensitization of capsaicin responses in rat sensory neurons. CFA-induced inflammatory thermal hyperalgesia in OVX-E rat hindpaws was significantly reduced in a dose-dependent manner by the PRL-R antagonist at the 6h, but not the 24h time point. In contrast, PRL contributed to inflammatory thermal hyperalgesia in male rats at 24h, but not 6h. In summary, these findings indicate that inflammation leads to accumulation of endogenous PRL in female and male rats. Further, PRL acts as an inflammatory mediator at different time points for female and male rats.

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).…”

“…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).…”

Prolactin receptor in regulation of neuronal excitability and channels

“…28 In contrast to these chronic inflammatory conditions, acute inflammation does not cause elevated levels of PRL in blood. 29 The second pathological condition associated with elevated levels of PRL is physiological and physical stress (i.e., trauma). Burn, 30 surgical procedures, 31,32 associated with increased PRL serum levels.…”

“…7,29,[36][37][38][39][40] Dual regulation of extra-pituitary PRL by estrogen and pathological condition is not well studied. Therefore, direct measurements on alterations in PRL concentrations in relevant parts of the nervous system triggered by pathological conditions are important to consider.…”