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Endomorphin-1 analogs with oligoarginine-conjugation at C-terminus produce potent antinociception with reduced opioid tolerance in paw withdrawal test.
Peptides ; 106: 96-101, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30016700
For clinical use, it is essential to develop potent endomorphin (EM) analogs with reduced antinociceptive tolerance. In the present study, the antinociceptive activities and tolerance development of four potent EM-1 analogs with C-terminal oligoarginine-conjugation was evaluated and compared in the radiant heat paw withdrawal test. Following intracerebroventricular (i.c.v.) administration, all analogs 1-4 produced potent and prolonged antinociceptive effects. Notably, analogs 2 and 4 with the introduction of D-Ala in position 2 exhibited relatively higher analgesic potencies than those of analogs 1 and 3 with ß-Pro substitution, consistent with their µ-opioid binding characteristic. In addition, at a dose of 50 µmol/kg, endomorphin-1 (EM-1) failed to produce any significant antinociceptive activity after peripheral administration, whereas analogs 1-4 induced potent antinociceptive effects with an increased duration of action. Herein, our results indicated the development of antinociceptive tolerance to EM-1 and morphine at the supraspinal level on day 7. By contrast, analogs 1-4 decreased the antinociceptive tolerance. Furthermore, subcutaneous (s.c.) administration of morphine at 50 µmol/kg also developed the antinociceptive tolerance, whereas the extent of tolerance developed to analogs 1-4 was largely reduced. Especially, analog 4 exhibited non-tolerance-forming antinociception after peripheral administration. The present investigation gave the evidence that C-terminal conjugation of EM-1 with oligoarginine vector will facilitate the development of novel opioid analgesics with reduced opioid tolerance.





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Arginina / Tolerância a Medicamentos / Analgésicos / Analgésicos Opioides Limite: Animais Idioma: Inglês Revista: Peptides Ano de publicação: 2018 Tipo de documento: Artigo País de afiliação: China