Lysosomal Ion Channel TRPML1 Contributes to Neuropathic Pain Associated With Diabetic Peripheral Neuropathy in Mice.

Neuropathic pain associated with diabetic peripheral neuropathy (DPN) is a common and hard-to-treat complication of diabetes. Ion channels of plasma membrane are major mechanisms and targets for DPN pain. This study explores the role of a major lysosomal ion channel, TRPML1, in DPN pain. Mouse models of DPN pain and TRPML1 knockout were combined with pharmacological inhibition and detection of molecular expression and function. Major findings included 1) BKS db/db increased expression and function of TRPML1 in dorsal root ganglion (DRG); 2) lysosomes of DRG neurons expressed functional TRPML1 currents; 3) global knockout (gKO) or conditional knockout (cKO) in DRG neurons of TRPML1 prevented mechanical allodynia in male mice fed a high-fat diet; 4) a TRPML1 inhibitor significantly reversed mechanical allodynia in BKS db/db mice through intraperitoneal injection and in streptozotocin (STZ) mice through intrathecal injection; and 5) gKO or astrocyte cKO of TRPML1 prevented STZ-induced mechanical allodynia in male and female mice. The results suggest that TRPML1 in DRG neurons and astrocytes contributes to type 2 and type 1 DPN pain, respectively (type 1 and type 2 DPN pain refer to neuropathic pain associated with type 1 diabetes and type 2 diabetes or pre-diabetes). This study may serve as a proof of concept to explore the role of lysosomal ion channels in painful DPN, painless DPN, and chronic pain. ARTICLE HIGHLIGHTS: A lysosomal ion channel, TRPML1, contributes to neuropathic pain associated with diabetic peripheral neuropathy (DPN). TRPML1 of dorsal root ganglion neurons contributes to type 2 DPN pain. Astrocyte TRPML1 contributes to type 1 DPN pain. Lysosomal ion channels may be novel mechanisms and targets for DPN pain.