Inhibition of nociceptive responses after systemic administration of amidated kyotorphin
dc.contributor.author
dc.date.accessioned
2015-02-03T15:50:17Z
dc.date.available
2015-02-03T15:50:17Z
dc.date.issued
2011
dc.identifier.issn
0007-1188
dc.identifier.uri
dc.description.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
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Wiley
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Reproducció digital del document publicat a: http://dx.doi.org/10.1111/j.1476-5381.2011.01290.x
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© British Journal of Pharmacology, 2011, vol. 163, p. 964-973
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dc.title
Inhibition of nociceptive responses after systemic administration of amidated kyotorphin
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.embargo.terms
Cap
dc.relation.projectID
info:eu-repo/grantAgreement/EC/FP7/230654/EU/Selected peptides as drug candidates directed to pain and neurodegeneration/PEP2BRAIN
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.identifier.idgrec
014914
dc.relation.FundingProgramme
dc.relation.ProjectAcronym
dc.identifier.eissn
1476-5381