We have previously demonstrated that trinitrobenzene sulfonic acid (TNBS)-induced colitis in guinea pig is associated with hyperexcitability of myenteric AH neurones, enhanced synaptic activity in the myenteric plexus, increased serotonin (5-HT) availability in the mucosa, and decreased propulsive motor activity. The current study tested the hypothesis that activation of cyclooxygenase (COX) contributes to these alterations in bowel functions. Inhibition of COX-2 with DFU, but not COX-1 with SC-560, restored to normal levels the electrical properties of myenteric AH neurones, the proportion of S neurones exhibiting slow EPSPs, and the rate of propulsive motor activity. Neither inhibitor was effective in altering the level of inflammation, the increased availability of mucosal 5-HT, or the enhanced fast EPSPs in myenteric AH and S neurones. COX-2 expression is enhanced in the myenteric plexus and cells within the smooth muscle layers during colitis, likely reflecting the site at which COX-2 inhibition acts to allow recovery of motor function. In support of this concept, COX-1, but not COX-2 inhibition was effective in restoring normal mucosal prostaglandin levels. These results indicate that the various changes that occur in the motor neural pathways of the distal colon in TNBS-induced colitis do not involve a single neuroimmune mechanism. COX-2 activation is a critical step in the enhanced excitability of AH neurones as well as diminished propulsive motility in TNBS colitis, whereas other yet to be resolved pathways, that do not involve COX-1 or COX-2 activation, lead to altered 5-HT content in the mucosa and an augmentation of fast EPSPs.