Intranasal Administration of the Combination of Dextro-Ketamine and Dexmedetomidine for Treatment of Diabetic Neuropathic Pain in Rats

Abstract

Susumu Zapata Sudo,1,* Tadeu Lima Montagnoli,2,* Bruno Eduardo Dematté,3 Aimeé Diogenes Santos,2 Margarete Manhães Trachez,4 Fernanda Gubert,5 Rosalia Mendez-Otero,6 Gisele Zapata-Sudo1– 5 1Programa de Pós-Graduação em Medicina (Cirurgia Geral), Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 2Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 3Programa de Pós-Graduação em Medicina (Cardiologia), Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 4Instituto do Coração Edson Saad, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 5Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 6Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil*These authors contributed equally to this workCorrespondence: Gisele Zapata-Sudo, Instituto do Coração Edson Saad, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil, Email [email protected]; [email protected]: Diabetes mellitus (DM) has become a public health problem, which is associated with high morbidity and mortality, due to the chronic complications, such as diabetic neuropathy. Current recommendations for the treatment of neuropathic pain achieve a reduction of 30% in only 30% of cases. Therefore, it is necessary to identify new therapeutic approaches to improve the quality of life of diabetic patients.Methods: This work evaluated the antinociceptive effect of intranasal administration of the combination of dextro-ketamine (keta), a non-competitive glutamatergic receptor antagonist, and dexmedetomidine (DEX), a selective alpha2-adrenergic agonist, in rats with neuropathic pain induced by streptozotocin-DM.Results: The thermal hyperalgesia and mechanical allodynia observed in DM model are reduced with the intranasal administration of the combination of keta and DEX (200 + 0.10 μg/kg) after 3 days of treatment. The antinociceptive action could be due to reduction of Ca2+ influx with lower glutamate release and reduced excitability through the activation of alpha2-adrenergic receptors by DEX and reduction of NMDA receptor activation by glutamate with lower excitability due to the antagonism produced by keta. DM induced increased expression of glial fibrillary acid protein (GFAP) and tumor necrosis factor-alpha (TNF-alpha) detected by immunohistochemistry, indicating greater astrocyte activity and intense inflammatory response. Intranasal administration for 10 days of the combination of low doses of keta and DEX promoted an intense decrease in the expression of both GFAP and TNF-alpha, indicating lower activation of astrocytes in the spinal cord and reduced production and release of TNF-alpha, favoring the reduction of inflammation.Conclusion: Intranasal administration of low doses of keta with DEX could be a new therapeutic approach to reduce neuropathic pain and consequently improve the quality of life of diabetic patients.Keywords: diabetes, neuropathic pain, dextro-ketamine, dexmedetomidine

Keywords

• diabetes
• neuropathic pain
• dextro-ketamine
• dexmedetomidine