title: Mechanisms of inhibitory action of TRK-130 (Naltalimide), a μ-opioid receptor partial agonist, on the micturition reflex.
abstract: OBJECTIVE
  To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex.
  
  
  METHODS
  The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats.
  
  
  RESULTS
  TRK-130 (0.001-0.01 mg/kg, iv) dose-dependently inhibited RBCs, which was dose-dependently antagonized by naloxone; however, the antagonism susceptibility was different from morphine (1 mg/kg, iv). The minimum effective dose (0.003 mg/kg) of TRK-130 remained similar in spinal cord-transected animals. TRK-130 (0.0025 mg/kg, iv) increased bladder capacity without changing the voiding efficiency, maximum flow rate, and intravesical pressure at the maximum flow rate, whereas oxybutynin (1 mg/kg, iv) increased the bladder capacity but affected the other parameters. TRK-130 (0.005 mg/kg, iv) did not produce significant changes on the bladder contractions induced by peripheral stimulation of the pelvic nerve, while oxybutynin (1 mg/kg, iv) significantly suppressed the bladder contractions.
  
  
  CONCLUSIONS
  These results suggest that TRK-130 enhances the bladder storage function by modulating the afferent limb of the micturition reflex through µ-opioid receptors in the spinal cord. TRK-130 could be a more effective and safer therapeutic agent with a different fashion from antimuscarinics and conventional opioids for overactive bladder.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan. Morihiro_Fujimura@nts.toray.co.jp.
authors.forename: Morihiro
authors.identifier: http://orcid.org/0000-0002-0548-6981
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Izumimoto
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Sayoko
authors.initials: S
authors.lastname: Kanie
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kobayashi
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yoshikawa
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Momen
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Mikito
authors.initials: M
authors.lastname: Hirakata
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Komagata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okanishi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Iwata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
authors.affiliation: Departments of Urology and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D006168:Guinea Pigs; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology; D009019:Morphinans / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010525:Peripheral Nerves; D010797:Phthalimides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists; D012018:Reflex / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000503:physiopathology; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D014554:Urination / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D008333:Mandelic Acids; D009019:Morphinans; D018727:Muscarinic Antagonists; C000591921:N-(17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl)phthalimide; D009292:Narcotic Antagonists; D010797:Phthalimides; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; C005419:oxybutynin
keywords: Overactive bladder; Spinal; Supraspinal; TRK-130 (Naltalimide); Urodynamics; µ-Opioid receptor partial agonist