acid-phosphatase and Neuralgia

Adenosine receptor agonists have potent antinociceptive effects in diverse preclinical models of chronic pain. By contrast, the efficacy of adenosine and adenosine receptor agonists in treating pain in humans is unclear. Two ectonucleotidases that generate adenosine in nociceptive neurons were recently identified. When injected spinally, these enzymes have long-lasting adenosine A(1) receptor-dependent antinociceptive effects in inflammatory and neuropathic pain models. Furthermore, recent findings indicate that spinal adenosine A(2A) receptor activation can enduringly inhibit neuropathic pain symptoms. Collectively, these studies suggest the possibility of treating chronic pain in humans by targeting specific adenosine receptor subtypes in anatomically defined regions with agonists or with ectonucleotidases that generate adenosine.

Topics: 5'-Nucleotidase; Acid Phosphatase; Acupuncture Therapy; Adenosine; Adenosine Monophosphate; Analgesics; Animals; Humans; Hyperalgesia; Inflammation; Neuralgia; Nociceptors; Protein Tyrosine Phosphatases; Purinergic P1 Receptor Agonists; Receptors, Purinergic P1; Recombinant Proteins

Although electroacupuncture is widely used in chronic pain management, it is quite controversial due to its unclear mechanism. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs).. We applied EA in male C57 mice subjected to chronic constriction injury (CCI) and assessed extracellular ATP and 5'-nucleotidease expression in DRGs. Specifically, we used a luminescence assay, quantitative reverse transcriptase-polymerase chain reaction, Western blotting, immunohistochemistry and nociceptive-related behavioural changes to gather data, and we tested for effects after PAP expression was inhibited with an adeno-associated virus (AAV). Moreover, membrane PAP degradation was investigated in cultured DRG neurons and the inhibitory effects of EA on this degradation were assessed using immunoprecipitation.. EA treatment alleviated CCI surgery-induced mechanical pain hypersensitivity. Furthermore, extracellular ATP decreased significantly in both the DRGs and dorsal horn of EA-treated mice. PAP protein but not mRNA increased in L4-L5 DRGs, and inhibition of PAP expression via AAV microinjection reversed the analgesic effect of EA. Membrane PAP degradation occurred through a clathrin-mediated endocytosis pathway in cultured DRG neurons; EA treatment inhibited the phosphorylation of adaptor protein complex 2, which subsequently reduced the endocytosis of membrane PAP.. EA treatment alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice by inhibiting membrane PAP degradation via reduced endocytosis and subsequently promote ATP dephosphorylation in DRGs.. In a mouse model of chronic pain, electroacupuncture treatment increased levels of prostatic acid phosphatase (PAP: an ecto-nucleotidase known to relieve pain hypersensitivity) by inhibiting PAP degradation in dorsal root ganglions. This promoted extracellular ATP dephosphorylation, inhibited glia activation and eventually alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice. Our findings represent an important step forward in clarifying the mechanisms of pain relief afforded by acupuncture treatment.

Topics: Acid Phosphatase; Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Electroacupuncture; Ganglia, Spinal; Male; Mice; Neuralgia; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley

The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown.. Using resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior.. The activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats.. These data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.

Topics: Acid Phosphatase; Animals; Comorbidity; Depression; Histones; Interleukin-6; Neuralgia; Rats; STAT3 Transcription Factor; Tartrate-Resistant Acid Phosphatase

Neuropathic 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.. We used a resiniferatoxin (RTX)-induced small-fiber neuropathy model to examine whether functional PAP(þ) neurons are essential to maintain the analgesic effect. PAP(þ) neurons were categorized into small to medium neurons (25th-75th percentile: 17.1-23.7 mm); these neurons were slightly reduced by RTX (p¼0.0003). By contrast, RTX-induced activating transcription factor 3 (ATF3), an injury marker, in PAP(þ) neurons (29.0%5.6% vs. 0.2%0.2%, p¼0.0043), 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 (r¼0.62, p¼0.0062). 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.. This study revealed that functional PAP(þ) neurons are essential for the analgesic effect, which is mediated by NGF-trkA signaling.

Topics: Acid Phosphatase; Analgesics; Animals; Catechols; Diterpenes; Hyperalgesia; Mice; Models, Biological; Nerve Growth Factor; Neuralgia; Neurons; Phenotype; Receptor, trkA; Receptors, Purinergic P2X3; Signal Transduction

Prostatic acid phosphatase (PAP) is expressed in nociceptive dorsal root ganglion (DRG) neurons and functions as an ectonucleotidase that dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine to suppress pain via activating A1-adenosine receptor (A1R) in dorsal spinal cord. However, the effect of peripheral nerve injury on the expression of PAP has not been reported until now. In the present study we found that PAP expression in DRG neurons is significantly decreased from the 2nd day after peripheral nerve injury and reaches the bottom at the 14th. In addition, intrathecal PAP injection can reduce mechanical allodynia induced by spared nerve injury. Our findings suggest that the decrease of PAP is involved in pathophysiological mechanisms of neuropathic pain.

Topics: Acid Phosphatase; Animals; Down-Regulation; Ganglia, Spinal; Hyperalgesia; Immunohistochemistry; In Situ Hybridization; Male; Neuralgia; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Sensory Receptor Cells

Etodolac, a cyclooxygenase-2 inhibitor, may alleviate nociceptive pain and inhibit the activation of osteoclasts. The aim of the present study was to determine whether etodolac can alleviate heat-evoked hyperalgesia and investigate its possible protective effects on osteoporosis induced by chronic constriction injury (CCI) in rats. A CCI to the sciatic nerve was performed, after which the rats received etodolac orally in a volume of 2 ml at 0, 1, and 10 mg/kg/day for 1 to 5 weeks following surgery (experiment 1); at 0 and 10 mg/kg/day for 1 day to 5 weeks following surgery (experiment 2); and at 0 mg/kg/day for 1 to 5 weeks, 10 mg/kg/day for 1 to 2 weeks after surgery, or 10 mg/kg/day for 1 to 3 weeks after surgery (experiment 3). Paw withdrawal latency after exposure to heat, bone mineral content (BMC) and bone mineral density (BMD) in the whole tibial bone, and the number of tartrate resistant acid phosphate (TRAP)-positive multinucleated osteoclasts were measured. Etodolac alleviated heat-evoked hyperalgesia in the CCI rats and the increase in number of TRAP-positive multinucleated osteoclasts on the CCI-side was abrogated, however, it did not inhibit the decrease of BMC and BMD on the CCI-side. Our results suggest that etodolac is useful for treatment of neuropathic pain.

Topics: Acid Phosphatase; Animals; Bone Density; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Etodolac; Hyperalgesia; Isoenzymes; Ligation; Neuralgia; Osteoclasts; Osteoporosis; Pain Measurement; Peripheral Nerves; Peripheral Nervous System Diseases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Reaction Time; Sciatic Neuropathy; Tartrate-Resistant Acid Phosphatase; Up-Regulation