Posted by Lin et al. have recently reported on the mechanism of pain development and manipulation by methyl BCD [1]. A mouse model of drug-induced neuropathy mimicking the characteristics of patients with small-fiber neuropathy was used. Small fiber neuropathy occurs when the small fibers of the peripheral nervous system are damaged. This condition causes sensory symptoms such as pain, burning and tingling. Mice were treated with methyl BCD in four doses through an intrathecal lumbar puncture (1 μg/5 μl, cumulative 5 μg/mouse).
Specialized microdomains which have cholesterol-rich membrane regions containing transient receptor potential vanilloid subtype 1 (TRPV1) are involved in pain development. The other player of pain nociception is prostatic acid phosphatase (PAP), a membrane bound ectonucleosidase, which can hydrolyse adenosine monophosphate to the antinociceptive agonist adenosine. Lin et al. found that both proteins are located within the same cholesterol-rich membrane microdomain suggesting that they are involved in intracellular signaling transduction during normal neurophysiology. The molecular intervention between TRPV1 and PAP involves a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) signal. Applying methyl BCD transiently depleted cholesterol thus disrupted the integrity of microdomains containing TRPV1 and adenosine signal molecules resulting in delayed development of pain.
Pain control targeting microdomains in the plasma membrane is a new direction for research that has received only limited attention. The effect of methyl BCD on pain transduction was attributed to the disruption of membrane integrity via depletion of membrane cholesterol. Recurrence of pain was observed because of dynamic replenishment of cholesterol from intracellular stores [2]. It means that the effect of methyl BCD was transient and therefore multiple doses of methyl BCD are required.
Lin, C.L., Chang, C.H., Chang,Y.S., Lu, S.C., Hsieh, Y.L.: Treatment with methyl-β-cyclodextrin prevents mechanical allodynia in resiniferatoxin neuropathy in a mouse model. Biology Open 2019, 8: bio039511 doi: 10.1242/bio.039511
Mahammad, S. and Parmryd, I.: Cholesterol homeostasis in T cells. Methyl-beta-cyclodextrin treatment results in equal loss of cholesterol from Triton X-100 soluble and insoluble fractions. Biochim. Biophys. Acta 2008, 1778, 1251-1258. doi:10.1016/j.bbamem.2008.02.010