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Title: Inhibition of nociceptive responses after systemic administration of amidated kyotorphin
Authors: Ribeiro, M. M. B.
Pinto, A.
Pinto, M.
Heras, M.
Martins, I.
Correia, A.
Bardaji, E.
Tavares, I.
Castanho, M.
Keywords: Kyotorphin
Blood–brain barrier
Issue Date: 2011
Publisher: Wiley-Blackwell
Citation: British Journal of Pharmacology (2011) 163 964–973
Abstract: BACKGROUND AND PURPOSE Kyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood–brain barrier (BBB) and detract from the possible clinical use of KTP as an analgesic. In this study, we aimed to increase the lipophilicity of KTP by amidation and to evaluate the analgesic efficacy of a new KTP derivative (KTP-amide – KTP-NH2). EXPERIMENTAL APPROACH We synthesized KTP-NH2. This peptide was given systemically to assess its ability to cross the BBB. A wide range of pain models, including acute, sustained and chronic inflammatory and neuropathic pain, were used to characterize analgesic efficacies of KTP-NH2. Binding to opioid receptors and toxicity were also measured. KEY RESULTS KTP-NH2, unlike its precursor KTP, was lipophilic and highly analgesic following systemic administration in several acute and chronic pain models, without inducing toxic effects or affecting motor responses and blood pressure. Binding to opioid receptors was minimal. KTP-NH2 inhibited nociceptive responses of spinal neurons. Its analgesic effects were prevented by intrathecal or i.p. administration of naloxone. CONCLUSIONS AND IMPLICATIONS Amidation allowed KTP to show good analgesic ability after systemic delivery in acute and chronic pain models. The indirect opioid-mediated actions of KTP-NH2 may explain why this compound retained its analgesic effects although the usual side effects of opioids were absent, which is a desired feature in next-generation pain medications. Abbreviations BBB, blood–brain barrier; BOP, benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumfluorophosphate; CFA, complete Freund’s adjuvant; DMF, N,N-dimethylformamide; HRMS-ESI, high-resolution mass spectra under electrospray ionization; i.t., intrathecal; KTP, kyotorphin; KTP-NH2, kyotorphin-amide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NMM, N-methylmorpholine; NOP, N/OFQ opioid receptor; PBS, phosphate-buffered saline; SNI, spared nerve injury
Description: © 2011 The Authors © 2011 The British Pharmacological Society
MMB Ribeiro, M Pinto, M Heras, A Correia, E Bardaji, I Tavares and MARB Castanho are named as inventors in the patent WO2009/123487 A1.
Peer review: yes
URI: hhtp://
ISSN: 0007-1188
Publisher Version: The definitive version is available at
Appears in Collections:IMM - Artigos em Revistas Internacionais

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