Wnt signaling is involved in crotalphine-induced analgesia in a rat model of neuropathic pain

Autor(es)

Hosch, Natalia G. ; Martins, Barbara B. ; Alcantara, Queren A. ; Bufalo, Michelle Cristiane ; Neto, Beatriz S. ; Chudzinki-Tavassi, Ana Marisa ; Santa-Cecilia, Flavia V. ; Cury, Yara ; Zambelli, Vanessa O.

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 959, p. 13-pg., 2023-10-01.

Resumo

The aberrant activation of Wnt/beta-catenin and atypical Wnt/Ryk signaling pathways in the spinal cord is critical for the development and maintenance of neuropathic pain. Crotalphine is a structural analog to a peptide first identified in Crotalus durissus terrificus snake venom, which induces antinociception by activating kappa-opioid and CB2 cannabinoid receptors. Consistent with previous data, we showed that the protein levels of the ca-nonical Wnt/beta-catenin and the atypical Wnt/Ryk signaling pathways are increased in neuropathic rats. Impor-tantly, the administration of crotalphine downregulates these protein levels, including its downstream cascades, such as TCF4 from the canonical pathway and NR2B glutamatergic receptor and Ca2+-dependent signals, via the Ryk receptor. The CB2 receptor antagonist, AM630, abolished the crotalphine-induced atypical Wnt/Ryk signaling pathway activation. However, the selective CB2 agonist affects both canonical and non-canonical Wnt signaling in the spinal cord. Next, we showed that crotalphine blocked hypersensitivity and significantly decreased the concentration of IL-1a, IL-1 beta, IL-6, IL-10, IL-18, TNF-a, MIP-1a and MIP-2 induced by intrathecal injection of exogenous Wnt-3a agonist. Taken together, our findings show that crotalphine induces analgesia in a neuropathic pain model by down-regulating the canonical Wnt/beta-catenin and the atypical Wnt/Ryk signaling pathways and, consequently controlling neuroinflammation. This effect is, at least in part, mediated by CB2 receptor activation. These results open a perspective for new approaches that can be used to target Wnt signaling in the context of chronic pain.Perspective: Our work identified that crotalphine-induced activation of CB2 receptors plays a critical role in the impairment of Wnt signaling during neuropathic pain. This work suggests that drugs with opioid/cannabinoid activity may be a useful strategy to target Wnt signaling in the context of chronic pain. (AU)

• Processo FAPESP: 20/04998-0 - Participação da aldeído desidrogenase-2 na neuroinflamação induzida pela constrição do nervo isquiático
• Beneficiário: Queren Apuque Alcantara
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 15/50040-4 - Rational approach for searching molecular targets involved in inflammatory events and cell survival
• Beneficiário: Ana Marisa Chudzinski-Tavassi
• Modalidade de apoio: Auxílio à Pesquisa - Programa Centros de Pesquisa em Engenharia
• Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
• Beneficiário: Hugo Aguirre Armelin
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 20/13139-0 - Centro de Excelência na Descoberta de Novos Alvos
• Beneficiário: Ana Marisa Chudzinski-Tavassi
• Modalidade de apoio: Auxílio à Pesquisa - Programa Centros de Pesquisa em Engenharia