| Full text | |
| Author(s): |
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.
Total Authors: 9
|
| Document type: | Journal article |
| Source: | European Journal of Pharmacology; v. 959, p. 13-pg., 2023-10-01. |
| Abstract | |
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) | |
| FAPESP's process: | 20/04998-0 - Role of aldehyde dehydrogenase 2 in neuroinflammation induced by chronic constriction of the sciatic nerve |
| Grantee: | Queren Apuque Alcantara |
| Support Opportunities: | Scholarships in Brazil - Master |
| FAPESP's process: | 15/50040-4 - Rational approach for searching molecular targets involved in inflammatory events and cell survival |
| Grantee: | Ana Marisa Chudzinski-Tavassi |
| Support Opportunities: | Research Grants - Applied Research Centers Program |
| FAPESP's process: | 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling |
| Grantee: | Hugo Aguirre Armelin |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |
| FAPESP's process: | 20/13139-0 - Centre of Excellence in New Target Discovery |
| Grantee: | Ana Marisa Chudzinski-Tavassi |
| Support Opportunities: | Research Grants - Applied Research Centers Program |