Treatment with methyl-β-cyclodextrin prevents mechanical allodynia in resiniferatoxin neuropathy in a mouse model

• Published in: Biology open 2019-01, Vol.8 (1)
• Main Authors: Lin, Chih-Lung, Chang, Chin-Hong, Chang, Ying-Shuang, Lu, Shui-Chin, Hsieh, Yu-Lin
• Format: Article
• Language: English
• Subjects: 5-bisphosphate; Acid phosphatase; Adenosine; Analgesics; Capsaicin receptors; Chemical compounds; Cholesterol; Cyclodextrins; Depletion; Dorsal root ganglia; Ectonucleotidase; Hypersensitivity; Immunohistochemistry; Integrity; Membranes; Methyl-β-Cyclodextrin; Neurodegeneration; Neuropathy; Pain; Pain perception; Pharmaceuticals; Phosphatidylinositol 4; Phosphatidylinositol 4,5-diphosphate; Polyimide resins; Prostatic acid phosphatase; Resiniferatoxin; Signal transduction; Signaling; Small-fiber neuropathy; Transient receptor potential proteins; Transient receptor potential vanilloid subtype 1
• ISSN: 2046-6390; 2046-6390
• DOI: 10.1242/bio.039511

Specialized microdomain which is cholesterol-rich membrane regions contains transient receptor potential vanilloid subtype 1 (TRPV1) is involved in pain development. Our previous studies have demonstrated that the depletion of prostatic acid phosphatase (PAP), a membrane-bound ectonucleotidase, and disordered adenosine signaling reduce the antinociceptive effect. The role of membrane integrity in the PAP-mediated antinociceptive effect in small-fiber neuropathy remains unclear, especially with respect to whether TRPV1 and PAP are colocalized in the same microdomain which is responsible for PAP-mediated antinociception. Immunohistochemistry was conducted on the dorsal root ganglion to identify the membrane compositions, and pharmacological interventions were conducted using methyl-β-cyclodextrin (MβC)-a membrane integrity disruptor that works by depleting cholesterol-in pure small-fiber neuropathy with resiniferatoxin (RTX). Immunohistochemical evidence indicated that TRPV1 and PAP were highly colocalized with flotillin 1 (66.7%±9.7%) and flotillin 2 (73.7%±6.0%), which reside in part in microdomain. MβC mildly depleted PAP, which maintained the ability to hydrolyze phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and delayed the development of mechanical allodynia. MβC treatment had no role in thermal transduction and neuronal injury following RTX neuropathy. In summary, this study demonstrated the following: (1) membrane cholesterol depletion preserves PAP-mediated antinociception through PI(4,5)P2 hydrolysis and (2) pain hypersensitivity that develops after TRPV1(+) neuron depletion-mediated neurodegeneration following RTX neuropathy is attributable to the downregulation of PAP analgesic signaling.