Neurokinin A (NKA) is an important spasmogen in human colon. We examined inflammatory disease-related changes in the tachykinin NK 2 receptor system in human sigmoid colon circular muscle, using functional, radioligand binding, and quantitative reverse transcription-polymerase chain reaction methods. In circular muscle strips, indomethacin enhanced contractile responses to NKA (p Ͻ 0.01) and to the NK 2 receptor-selective agonist [Lys 5 ,MeLeu 9 ,Nle 10 ]-NKA(4 -10) (p Ͻ 0.05) in both normal and acute diverticular disease (DD) specimens, indicating NK 2 receptor-mediated release of relaxant prostanoids. Contractile responses to both tachykinins were reduced in strips from DD (p Ͻ 0.001) and ulcerative colitis (UC) (p Ͻ 0.05) specimens. Responses to acetylcholine were no different in other strips from the same disease patients, demonstrating that the change in responsiveness to tachykinins in disease is specifically mediated by the NK 2 receptor. In membranes from UC specimens, receptor affinity for 125 I-NKA (median K D 0.91 nM, n ϭ 16) was lower (p Ͻ 0.01) than that in age-matched control specimens (K D 0.55 nM, n ϭ 40), whereas K D (0.65 nM, n ϭ 28) in DD was no different from control. No disease-related changes in receptor number (B max ) were found (mean, 2.0 -2.5 fmol/mg of wet weight tissue), suggesting that the reduced contractile responses in disease are not due to a loss of receptor number. Different mechanisms may account for the reduced contractility in DD compared with UC. A gender-related difference in receptor density was seen in controls, with B max lower in females (1.77 fmol/mg, n ϭ 15) than in males (2.60 fmol/mg, n ϭ 25, p ϭ 0.01). In contrast, no gender-related differences were seen in NK 2 receptor mRNA in control colonic muscle, indicating that the gender difference is a post-translational event.