Effect of a kappa-opioid agonist, i.v. JNJ-38488502, on sensation of colonic distensions in healthy male volunteers.

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.

Comparison of mathematical methods for calculating colonic compliance in humans: power exponential, computer-based and manual linear interpolation models.

Measuring compliance allows differentiation of sensory changes from changes in thresholds because of altered compliance. As compliance of the colorectum is sigmoidal, a power exponential analysis was recommended. We aimed to develop and validate simpler measurements of compliance. Forty subjects (23 female, 17 male) underwent colonic barostat procedures comparing dronabinol vs placebo. Results of the effects on compliance were reported elsewhere. Compliance was determined as volume response to pressures ranging from 0 to 36 mmHg. Pressures corresponding to 10%, 50% and 90% (Pr10, Pr50 and Pr90) of maximum volume at 36 mmHg were estimated using a power exponential model, computer-based and manual linear interpolation. Data were compared and concordance evaluated. Pr50 and Pr90 were not significantly different by all methods for baseline and post-treatment. Respectively, concordance correlation coefficients were: pretreatment, 0.879, 0.464 and post-treatment, 0.879, 0.623. There is larger variation in Pr10 comparing all methods and manual calculations allow for the closest fit to the data. Concordance correlation coefficients were pretreatment = 0.189 and post-treatment = 0.322. There were no gender differences in compliance measurements. Results of compliance are highly concordant amongst all models. However, computer-based or manual interpolations appear superior to power exponential models for estimating Pr10.