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

Abstract

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.