Home Blog of Signal Transduction Neuronal Signaling BACE Spinal beta-amyloid1-42 acts as an endogenous analgesic peptide in CCI-induced neuropathic pain

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Spinal beta-amyloid1-42 acts as an endogenous analgesic peptide in CCI-induced neuropathic pain

Background: The mechanism for reduced pain sensitivity associated with Alzheimer's disease (AD) has not been illustrated. We hypothesize that amyloid beta 1-42 (Aβ1-42) in the spinal cord acts as an endogenous analgesic peptide to suppress pain induced by nerve injury.

Methods: We used chronic constriction injury of the sciatic nerve (CCI) to produce neuropathic pain in Sprague-Dawley rats. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to determine the level of Aβ1-42, the expression of Wnt3a/5b and glial activation in the spinal cord. Western blotting was used to determine the expression of interleukins, the phosphorylation of NR2B and ERK1/2, and the nuclear accumulation of transcriptional factors YAP/TAZ. Thermal hyperalgesia and mechanical allodynia were assessed after CCI and pharmacological manipulations through intrathecal administration.

Results: Nerve injury increases spinal level of Aβ1-42, while intrathecal administration of MK-8931 reduces the level of Aβ1-42 and facilitates mechanical allodynia. Intrathecal administration of Aβ1-42 suppresses pain behaviors in the early and late phases of neuropathy. Spinal administration of Aβ1-42 regulates the expression of interleukins, reducing glial activation and phosphorylation of NR2B and ERK1/2 in the spinal cord of CCI rats. Furthermore, intrathecal administration of Aβ1-42 decreases Wnt5b expression and suppresses the nuclear accumulation of YAP and TAZ. Blocking the interaction between Aβ1-42 and Frizzled receptors by cSP5 reverses the analgesic effects of Aβ1-42.

Conclusions: These findings suggest that spinal Aβ1-42 acts as an endogenous analgesic peptide through regulating cytokines and Wnt pathways. This study may provide a potential target for the development of novel analgesic peptides.

Significance: This study provides an explanation of reduced pain sensitivity associated with Alzheimer's disease. Furthermore, our findings propose a possible physiological function of beta-amyloid1-42 to regulate pain. This study may provide a potential target for the development of novel analgesics based on an existing endogenous peptide.

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