The role of endogenous opioids in the control of gastrointestinal motility: predictions from in vitro modelling

Abstract

Gastrointestinal motility can be assessed in vitro by investigating the effects of drugs or gene knockouts on intestinal propulsion, and on neurone-mediated responses evoked by electrical field stimulation (EFS). The latter predominantly measure enteric motor activity and can detect prokinetic activity of exogenous agents. Some evidence suggests that naloxone has prokinetic activity when evaluated for an ability to modulate responses to EFS, but the effects are inconsistent across different species or intestinal regions. Models of intestinal peristalsis measure an integrated sensory-motor nerve function and possess more intact neuro-neuronal connections. In such preparations, the effects of naloxone also suggest a prokinetic property but again, this is inconsistent. By contrast, consistent prokinetic activity of naloxone is apparent in models where peristalsis is compromised by drug-induced suppression of motor nerve activity or by modulation of endogenous processes using receptor antagonists or inappropriate intraluminal distension. These data suggest that endogenous opioids play little or no role in normal intestinal physiology, but suppress intestinal motility when motor function is compromised. Consequently, drugs that antagonize opioid receptors may exert prokinetic activity in conditions where intestinal motility is reduced, such as constipation. Further work is required to elucidate the opiate receptor(s) involved.

Treatment of opioid-induced gut dysfunction

“…Inhibition of excitatory neural inputs is associated with inhibition of the release of excitatory transmitters such as acetylcholine and blockade of distension-induced peristaltic contractions, whereas blockade of inhibitory neural inputs results in depression of NO release from inhibitory motor neurons, disinhibition of GI muscle activity, elevation of resting muscle tone and non-propulsive motility patterns [6,8,13,21,23,24]. A direct activation of the interstitial cell-muscle network has also been envisaged [25,26].…”

“…When released from enteric neurons, it is likely that opioid peptides play a mediator role in the regulation of propulsion and secretion [2,5,6,8,9,[19][20][21]. This conjecture is reflected by the actions of exogenous opioid receptor agonists and antagonists on GI function (Figure 1).…”

“…This concept is primarily based on the ability of opioid receptor antagonists to influence GI physiology and pathophysiology; for example, distension-evoked peristalsis can be facilitated by the pan-opioid receptor antagonist naloxone in various preparations of the guinea-pig, rabbit, cat and rat isolated small intestine [6,8,19,20]. In the guinea-pig small intestine, the effect of naloxone is mimicked by selective antagonists at µ-(cyprodime) and κ-(norbinaltorphimine) opioid receptors, but not by antagonism at δ-opioid receptors [20].…”

“…This pharmacological profile reflects the significant role that neurons play in GI function and the fact that many of the transmitters and transmitter receptors present in the brain have also been localised to the gut. This is particularly true for opioid receptors and adrenoceptors whose activation by opiates and catecholamines, respectively, interferes with pathways of the enteric nervous system that regulate motility and secretion [1][2][3][4][5][6][7][8][9].…”

The influence of opioids on gastric function: experimental and clinical studies

“…(74) Inhibition of endogenous peptides, i.e. through blockage of opioid receptors, might therefore act prokinetically under conditions of disrupted motility (75).…”