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

Chih-Lung Lin; Chin-Hong Chang; Ying-Shuang Chang; Shui-Chin Lu; Yu-Lin Hsieh

doi:10.1242/bio.039511

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

Biol Open. 2019 Jan 14;8(1):bio039511. doi: 10.1242/bio.039511.

Authors

Chih-Lung Lin^{1

2}, Chin-Hong Chang³, Ying-Shuang Chang⁴, Shui-Chin Lu⁵, Yu-Lin Hsieh^{6

7}

Affiliations

¹ Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
² Faculty of Medicine, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
³ Department of Surgery, Chi Mei Medical Center, Tainan 71004, Taiwan.
⁴ Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁵ Department of Medical Research, Ultrastructural Laboratory, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
⁶ Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ylhsieh@kmu.edu.tw.
⁷ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.

Abstract

Specialized microdomains which have cholesterol-rich membrane regions contain transient receptor potential vanilloid subtype 1 (TRPV1) are 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 the 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.

Keywords: 5-bisphosphate; Cholesterol; Methyl-β-cyclodextrin; Phosphatidylinositol 4; Prostatic acid phosphatase; Small-fiber neuropathy; Transient receptor potential vanilloid subtype 1.