Activation and expression of μ-calpain in dorsal root contributes to RTX-induced mechanical allodynia

Abstract

BackgroundCalpain is a calcium-dependent cysteine protease, and inhibition of calpain by pre-treatment with MDL28170 attenuated the rat mechanical allodynia in a variety of pain models. Postherpetic neuralgia (Shingles) is a neuropathic pain conditioned with the presence of profound mechanical allodynia. Systemic injection of resiniferatoxin can reproduce the clinical symptoms of postherpetic neuralgia. In this study, we determined to study whether activation of calpain contributes to cleave the myelin basic protein of dorsal root and is involved in resiniferatoxin-induced mechanical allodynia of postherpetic neuralgia animal model.ResultsResiniferatoxin up-regulated the expression and activation of µ-calpain in dorsal root. The expression of µ-calpain was located in Schwann cell of dorsal root, and resiniferatoxin increased the expression of µ-calpain in Schwann cell in L4–L6 dorsal root at six weeks after injection. Resiniferatoxin also induced myelin basic protein degradation in L4–L6 dorsal root at six weeks after injection. Moreover, intraperitoneal injection of calpain inhibitor MDL28170 prevented the degradation of myelin basic protein and then reduced the sprouting of myelinated afferent fibers into spinal lamina II, thus relieving resiniferatoxin-induced mechanical allodynia.ConclusionsUp-regulation and activation of µ-calpain located in Schwann cell may be the mechanism underlying resiniferatoxin-mediated proteolysis of myelin basic protein in dorsal root. Calpain inhibitor MDL28170 prevents resiniferatoxin-induced sprouting of myelinated afferent fibers and mechanical allodynia through inhibition of degradation of the myelin basic protein in dorsal root. Our results indicate that inhibition of pathological µ-calpain activation may present an interesting novel drug target in the treatment of postherpetic neuralgia.

MBP‐activated autoimmunity plays a role in arsenic‐induced peripheral neuropathy and the potential protective effect of mecobalamin

“…Next, we tested the expression levels of MMP2 and μ‐calpain, which were reported to be involved in the cleavage of MBP 43,44 . After exposure to As, the expression levels of MMP2 and μ‐calpain increased noticeably as compared to the control, with significance in the increment of μ‐calpain expression level, and application of MeCbl in As‐treated group greatly counteracted the increases in μ‐calpain (F (3, 8) = 6.06, p = .02) expression levels.…”

“…In the present study, a significant upregulated μ‐calpain level was observed in As‐treated animals, accompanied with increased anti‐MBP antibody level in serum and declined mechanical withdrawal threshold, which was in accordance with the result of other researchers. For example, Yuan et al found that μ‐calpain released from Schwann cell contributed to cleave the MBP of dorsal root and was involved in resiniferatoxin‐induced mechanical allodynia 43 . In the case of traumatic brain injury, calpain could degrade MBP into N‐terminal fragments in the ipsilateral cortex and initiate T cell‐dependent secondary structural damage to the adjacent myelin membrane 58 .…”

“…For example, Yuan et al found that μ-calpain released from Schwann cell contributed to cleave the MBP of dorsal root and was involved in resiniferatoxin-induced mechanical allodynia. 43 In the case of traumatic brain injury, calpain could degrade MBP into Nterminal fragments in the ipsilateral cortex and initiate T celldependent secondary structural damage to the adjacent myelin membrane. 58 In contrast, inhibition of the over-activated calpain prevented axonal and myelin sheath damage as well as alleviated mechanical allodynia via alleviating the degradation of MBP.…”

“…58 In contrast, inhibition of the over-activated calpain prevented axonal and myelin sheath damage as well as alleviated mechanical allodynia via alleviating the degradation of MBP. 43,59 Furthermore, calpain probably plays a role in T cell bias because inhibition of calpain could decrease Th1 inflammatory cytokines and Th17 cell proliferation in PBMCs from MS patients. 60,61 Therefore, μ-calpain was probably an important contributor to MBP-related immune dysfunction and neuroinflammation.…”

100 Hz Electroacupuncture Alleviated Chronic Itch and GRPR Expression Through Activation of Kappa Opioid Receptors in Spinal Dorsal Horn

“…An Olympus BX51 fluorescence microscope was used to view the sections, and images were obtained using a Qimaging Camera and QCapture software as described before ( Yuan et al, 2017 ). A total of 5–6 sections from the skin or cervical cord were randomly selected in each mouse.…”