title: Effect of a kappa-opioid agonist, i.v. JNJ-38488502, on sensation of colonic distensions in healthy male volunteers.
abstract: Kappa-opioid receptors are located on visceral pain fibres. JNJ-38488502 is a highly selective tetrapeptide kappa-opioid agonist with little access to the central nervous system and low risk of central nervous system side effects. The aim of the study was to evaluate the effects of i.v. JNJ-38488502 on sensations, including pain, during colonic distension. In a single-centre study, 23 healthy adult males underwent a single-dose, randomized, double-blind crossover study of JNJ-38488502 (0.42 mg kg(-1) i.v. infusion) vs placebo on left colon compliance, sensory thresholds and ratings during standard distensions. One participant could not undergo sensation studies. In the other 22, JNJ-38488502 increased colonic compliance (pressure at half-maximum volume 17.9 +/- 0.8 mmHg) compared to placebo (21.6 +/- 0.9 mmHg, P = 0.007). There was no significant effect on sensory thresholds which, however, were not reached by 44 mmHg in >50% of participants in both treatment phases. There were no significant treatment effects on sensory ratings to distensions at 8, 16, 24, 32 and 36 mmHg above baseline operating pressure. JNJ-38488502 was associated with increased urine output and plasma prolactin, consistent with kappa-opioid receptor activation. This study concluded that i.v. JNJ-38488502 induced kappa-opioid effects, but did not attenuate colonic sensations following random order colonic distension. Further studies of effects on pain sensations in health and disease are required.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: B N
authors.initials: BN
authors.lastname: Floyd
authors.forename: M
authors.initials: M
authors.lastname: Camilleri
authors.forename: I
authors.initials: I
authors.lastname: Busciglio
authors.forename: S
authors.initials: S
authors.lastname: Sweetser
authors.forename: D
authors.initials: D
authors.lastname: Burton
authors.forename: G Y
authors.initials: GY
authors.lastname: Wong
authors.forename: S
authors.initials: S
authors.lastname: Kell
authors.forename: S
authors.initials: S
authors.lastname: Khanna
authors.forename: S
authors.initials: S
authors.lastname: Hwang
authors.forename: A R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D018592:Cross-Over Studies; D004108:Dilatation, Pathologic; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D017288:Pain Threshold / Q000187:drug effects*; D010919:Placebos; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012677:Sensation / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000081:Acetamides; D000701:Analgesics, Opioid; D010919:Placebos; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C092095:asimadoline