title: Inhibition of nociceptive responses after systemic administration of amidated kyotorphin.
abstract: OBJECTIVE
  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) ).
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisboa, Portugal.
authors.forename: M M B
authors.initials: MM
authors.lastname: Ribeiro
authors.forename: A
authors.initials: A
authors.lastname: Pinto
authors.forename: M
authors.initials: M
authors.lastname: Pinto
authors.forename: M
authors.initials: M
authors.lastname: Heras
authors.forename: I
authors.initials: I
authors.lastname: Martins
authors.forename: A
authors.initials: A
authors.lastname: Correia
authors.forename: E
authors.initials: E
authors.lastname: Bardaji
authors.forename: I
authors.initials: I
authors.lastname: Tavares
authors.forename: M
authors.initials: M
authors.lastname: Castanho
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002908:Chronic Disease; D004151:Dipeptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004723:Endorphins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000188:drug therapy*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism
chemical_list: D000700:Analgesics; D004151:Dipeptides; D004723:Endorphins; D011957:Receptors, Opioid; C561712:tyrosyl-argininamide; C019448:kyotorphin