title: Lack of a rewarding effect and a locomotor-enhancing effect of the selective μ-opioid receptor agonist amidino-TAPA.
abstract: OBJECTIVE
  Psychological dependence is one of the worst side effects of morphine. It limits the clinical availability of morphine and non-patient morphine users suffer from addiction. An analgesic, which is more potent than morphine but without the liability of psychological dependence, has long been sought in the clinic. We have recently developed a new μ-opioid receptor agonist, N(α)-amidino-Tyr-D-Arg-Phe-β-Ala (amidino-TAPA), as a potent analgesic with an antinociceptive profile that is distinct from morphine, including the release of endogenous κ-opioid peptides. The activation of κ-opioid receptors has been suggested to suppress the development of psychological dependence by μ-opioid receptor agonists. In the present study, the psychological dependence liability and the related locomotor-enhancing effect of amidino-TAPA were evaluated.
  
  
  RESULTS
  Amidino-TAPA injected subcutaneously produced an extremely potent and longer lasting antinociception than morphine in ddY mice, prodynorphin-knockout mice, and wild-type C57BL/6J mice. Unlike subcutaneously injected morphine, which had potent locomotor-enhancing and rewarding effects at antinociceptive doses in ddY mice, amidino-TAPA injected subcutaneously did not induce significant locomotor-enhancing and rewarding effects at antinociceptive or even higher doses in ddY mice. In wild-type C57BL/6J mice, amidino-TAPA showed the same pharmacological profile (potent antinociception, lack of locomotor-enhancing and rewarding effects) as in ddY mice. However, amidino-TAPA produced potent locomotor-enhancing and rewarding effects at antinociceptive doses in prodynorphin-knockout mice.
  
  
  CONCLUSIONS
  The present results suggest that amidino-TAPA is a potent analgesic without the liability of psychological dependence because it releases endogenous κ-opioid peptides.
authors.affiliation: Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Chizuko
authors.initials: C
authors.lastname: Watanabe
authors.forename: Shin
authors.initials: S
authors.lastname: Osada
authors.forename: Maya
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Yuta
authors.initials: Y
authors.lastname: Aoki
authors.forename: Sanae
authors.initials: S
authors.lastname: Natsui
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yonezawa
authors.forename: Syu-ichi
authors.initials: S
authors.lastname: Kanno
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sakurada
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004745:Enkephalins / Q000235:genetics; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D011498:Protein Precursors / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012201:Reward; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D004745:Enkephalins; C520058:N(alpha)-amidino-Tyr-D-Arg-Phe-beta-Ala; D009842:Oligopeptides; D011498:Protein Precursors; D017450:Receptors, Opioid, mu; D009020:Morphine; C033660:preproenkephalin