Paradoxical effects of opioids in suppression of colonic motility

Opiates slow colonic transit and cause constipation, effects traditionally attributed to suppression of excitatory cholinergic neurons through μ (MOR), δ (DOR), or κ (KOR) opioid receptors on myenteric neurons. However, the cellular mechanisms mediating opioid-induced constipation remain incompletely defined. We found that spontaneous enteric nitrergic motor inputs to mouse colon were reduced by opioid receptor agonists, leading to increased phasic contractions of colonic muscles, an effect abolished by pretreatment with tetrodotoxin, L-NNA, or apamin (in distal colon). Increased contractions in response to opioids are not easily explained by suppression of excitatory neural inputs, and spontaneous cholinergic motor inputs to colon were not suppressed by the MOR agonist Endomorphin-1 (EM-1). Consistent with these effects, MOR were expressed by many nitrergic neurons, and EM-1 reduced the asynchronous activity of nitrergic myenteric neurons during the period of tonic inhibition and the synchronized activity occurring normally just before neurogenic contractions. In addition to increasing phasic contractions, EM-1 enhanced Ca 2+ transients in interstitial cells of Cajal, depolarized membrane potentials of circular muscle cells, effects equivalent to the effects of tetrodotoxin. These are effects consistent with suppression of tonic inhibition. We also found that anterogradely propagating neurogenic contractions in intact colon were suppressed by receptor-specific MOR, DOR, and KOR agonists. Together, these observations demonstrate that opioid agonists suppress inhibitory rather than excitatory motor inputs to colonic muscles. Suppression of inhibitory motor inputs precludes the precisely timed cessation of enteric inhibition that causes poststimulus depolarization and peristaltic contractions.