What is the primary mechanism by which opioids induce constipation?

The primary mechanism by which opioids induce constipation is through the activation of mu (μ) opioid receptors in the gastrointestinal (GI) tract. Opioids, after systemic administration, bind to mu opioid receptors located in the enteric nervous system (ENS), which is the intrinsic nervous system of the GI tract, and on smooth muscle cells within the gut wall. Activation of these mu receptors in the GI tract causes a cascade of effects that lead to constipation. First, opioids decrease peristalsis, the wave-like muscle contractions that propel food and waste through the intestines. This reduced motility slows the transit time of fecal matter through the colon. Second, opioids increase the absorption of water from the intestinal contents back into the body. The slower transit time combined with increased water absorption results in drier, harder stools that are more difficult to pass. Third, opioids can increase the tone of the anal sphincter, making it more difficult to defecate. These effects are primarily mediated by the activation of mu opioid receptors in the GI tract, which disrupt the normal functioning of the enteric nervous system and alter the physiology of the intestines, leading to constipation. This opioid-induced constipation (OIC) is a common and often debilitating side effect of opioid therapy.