NGF-trkA signaling modulates the analgesic effects of prostatic acid phosphatase in resiniferatoxin-induced neuropathy

Abstract

BackgroundNeuropathic pain in small-fiber neuropathy results from injury to and sensitization of nociceptors. Functional prostatic acid phosphatase (PAP) acts as an analgesic effector. However, the mechanism responsible for the modulation of PAP neuropathology, which leads to loss of the analgesic effect after small-fiber neuropathy, remains unclear.ResultsWe used a resiniferatoxin (RTX)-induced small-fiber neuropathy model to examine whether functional PAP(+) neurons are essential to maintain the analgesic effect. PAP(+) neurons were categorized into small to medium neurons (25th–75th percentile: 17.1–23.7 µm); these neurons were slightly reduced by RTX (p = 0.0003). By contrast, RTX-induced activating transcription factor 3 (ATF3), an injury marker, in PAP(+) neurons (29.0% ± 5.6% vs. 0.2% ± 0.2%, p = 0.0043), indicating PAP neuropathology. Moreover, the high-affinity nerve growth factor (NGF) receptor (trkA) colocalized with PAP and showed similar profiles after RTX-induced neuropathy, and the PAP/trkA ratios correlated with the degree of mechanical allodynia (r = 0.62, p = 0.0062). The NGF inducer 4-methylcatechol (4MC) normalized the analgesic effects of PAP; specifically, it reversed the PAP and trkA profiles and relieved mechanical allodynia. Administering 2.5S NGF showed similar results to those of administering 4MC. This finding suggests that the analgesic effect of functional PAP is mediated by NGF-trkA signaling, which was confirmed by NGF neutralization.ConclusionsThis study revealed that functional PAP(+) neurons are essential for the analgesic effect, which is mediated by NGF-trkA signaling.

Pain management using photobiomodulation: Mechanisms, location, and repeatability quantified by pain threshold and neural biomarkers in mice

“…Similarly the requirement for some time to elapse (2–3 hours) before the analgesic effect manifested itself, also suggested that gene transcription and changes in protein expression were involved. This was corroborated by the histology findings in the excised DRG tissue that showed upregulation in the expression of PAP, a well-recognized analgesic mediator [17] that operates via NGF-trkA signaling [16]. Moreover changes were also observed in the number of tubulin varicosities and decreases in the expression levels of mGluR1 showing that distinct biochemical changes were occurring in the irradiated tissue.…”

Downregulation of adenosine and adenosine A1 receptor contributes to neuropathic pain in resiniferatoxin neuropathy

“…The activating transcription factor 3 (ATF3), an neuronal injury and pain marker, 12 was upregulated in remaining PAP(+) neurons, and the number of ATF3(+):PAP(+) neurons was correlated with the degree of neuropathic pain hypersensitivity. 41 Furthermore, PAP coexpressed with trkA in NGF-dependent nociceptors and NGF replenishment could rescue PAP neurons and normalized neuropathic pain behaviors. 41 Taken together, injured small-sized PAP(+) neurons were the major neurons responsible for the impairment of cellular analgesia, leading to neuropathic pain behaviors.…”

“…Resiniferatoxin neuropathy was induced by administering a single dose of an RTX (50 µg/kg; Sigma, St. Louis, MO) solution by using our previously established protocol. 12 , 13 , 18 , 41 Briefly, RTX was dissolved in a vehicle (10% Tween 80 and 10% ethanol in normal saline), and mice received the RTX solution through an intraperitoneal (i.p.) injection (RTX group).…”

“…Key components of this signaling pathway are (1) adenosine, which is a ligand for multiple adenosine receptors, 1 , 9 , 23 and (2) the transmembrane isoform of prostatic acid phosphatase (PAP), which hydrolyzes extracellular adenosine monophosphate (AMP) into adenosine using its ectonucleotidase properties. 35 , 37 , 47 Prostatic acid phosphatase is widely expressed by nonpeptidergic small-diameter nociceptors 40 , 41 and nerve growth factor (NGF)-dependent peptidergic nociceptors, 41 implying that PAP plays a key role in the maintenance of the delicate balance between nociception and analgesia. Inflammatory pain was alleviated by intrathecal (i.t.)…”

Tumor necrosis factor‐α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

“…RTX neuropathy was induced by administering a single dose of RTX (50 mg/kg, Sigma, St. Louis, MO, USA) solution by following our previously established protocol [13,14,20,21]. We divided the mice in the study into four groups.…”