Antiallodynic activity of leflunomide is partially inhibited by naltrexone and glibenclamide and associated with reduced production of TNF-alpha and CXCL-1

作者：Brito Ana Mercy S; Godin Adriana M; Augusto Paulo Sergio A; Menezes Raquel R; Melo Ivo S F; Dutra Marcela G M B; Costa Sarah O A M; Goulart Franciele A; Rodrigues Felipe F; Morais Marcela Isis; Machado Renes R; Coelho Marcio M^*

来源：European Journal of Pharmacology, 2018, 818: 17-25.

DOI：10.1016/j.ejphar.2017.10.026

• Leflunomide
• Pain
• Inflammation
• Opioidergic receptors
• ATP-sensitive potassium channels

Leflunomide, an immunosuppressive drug approved for the treatment of patients with rheumatoid arthritis, exhibits many mechanisms which may affect the nociceptive processing. Therefore, the present study aimed to evaluate the effect induced by leflunomide on the mechanical allodynia in models of inflammatory and neuropathic pain in mice and investigate mechanisms mediating such effects. Per os (p.o.) administration of leflunomide (25, 50 or 100 mg/kg) inhibited the inflammatory edema and mechanical allodynia induced by intraplantar carrageenan. Even ongoing inflammatory edema and mechanical allodynia were reduced by leflunomide. Previous administration of naltrexone (10 mg/kg, intraperitoneal) or glibenclamide (40 mg/kg, p.o.) partially attenuated leflunomide antiallodynic activity. A single administration of leflunomide (50 or 100 mg/kg, p.o.) also partially inhibited ongoing mechanical allodynia induced by chronic constriction injury (CCI) or repeated administrations of paclitaxel. The antiallodynic effect induced by leflunomide (50 or 100 mg/kg, p.o.) in the model of neuropathic pain induced by CCI was associated with reduced production of tumor necrosis factor-alpha both at the injury site and ipsilateral paw. Leflunomide also reduced production of the chemokine CXCL-1 at the paw ipsilateral to the injury site. Concluding, leflunomide partially inhibited ongoing mechanical allodynia in models of inflammatory and neuropathic pain. The antiallodynic effect was associated with activation of opioidergic receptors and ATP-sensitive potassium channels and reduced production of inflammatory mediators. These data indicate leflunomide as a drug that should be further investigated aiming to identify a new analgesic pharmacotherapy and reinforces repositioning as an important strategy to identify new uses for approved drugs.

• 出版日期2018-1-5