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Inhibition of nociceptive responses after systemic administration of amidated kyotorphin.

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-NH(2) ). EXPERIMENTAL APPROACH:We synthesized KTP-NH(2) . 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-NH(2) . Binding to opioid receptors and toxicity were also measured. KEY RESULTS:KTP-NH(2) , 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-NH(2) 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-NH(2) 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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Ribeiro MM,Pinto A,Pinto M,Heras M,Martins I,Correia A,Bardaji E,Tavares I,Castanho M

doi

10.1111/j.1476-5381.2011.01290.x

subject

Has Abstract

pub_date

2011-07-01 00:00:00

pages

964-73

issue

5

eissn

0007-1188

issn

1476-5381

journal_volume

163

pub_type

杂志文章

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