Neurokinin-1 receptor antagonism in a human model of visceral hypersensitivity


Prof Q. Aziz, GI Sciences Group, Clinical Sciences Building, Hope Hospital, Salford M6 8HD, UK.




Substance P acting via the neurokinin-1 receptor is involved in the development of hyperalgesia, although studies using neurokinin-1 receptor antagonists (NK-1RA) in human somatic pain have been disappointing.


To evaluate whether Substance P is involved in the development of human visceral pain/hyperalgesia using a selective NK-1RA.


Using a validated human model of acid-induced oesophageal allodynia, pain thresholds to electrical stimulation (mA) were measured in the proximal oesophagus and the foot (somatic control), pre- and for 4 h postdistal oesophageal acid in 14 healthy subjects, using a double-blind, randomized, two-period, crossover study. Measurements were taken on the third day of dosing with either an oral NK-1RA or matching placebo, with 2 weeks washout between periods.


Baseline pain threshold did not differ between treatments (proximal oesophagus 37 ± 7.4 mA NK-1RA vs. 38 ± 10.1 placebo P = 0.81, foot 40 ± 15 mA NK-1RA vs. 38 ± 14 placebo P = 0.68). NK-1RA did not attenuate the reduction in pain threshold in the proximal oesophagus postacid infusion (AUC−394 ± 279 NK-1RA vs. −262 ± 397 placebo P = 0.54).


The lack of effect of NK-1RA on oesophageal pain threshold in our model does not support a role for Substance P in the development of acid-induced oesophageal allodynia.