Regulation of neural responses in the canine pyloric sphincter by opioids

Abstract

1 Regulation of excitatory and inhibitory junction potentials (ej.ps and ij.ps) by opioid peptides was studied in isolated muscle strips from the pyloric sphincter of the dog.2 Methionine enkephalin (MetEnk; 1010 to 10-6 M) and enkephalin (DADLE; 10-" to 10-' M), a 6-specific opioid agonist, inhibited ij.ps and ej.ps recorded from cells in the myenteric and submucosal regions of the circular muscle layer. These compounds had no effect on resting potential or slow wave activity suggesting that the effects on junction potentials were not due to direct effects on smooth muscle cells. 3 MetEnk and DADLE caused similar effects on junction potentials in preparations in which the myenteric plexus was removed, suggesting that opioids inhibit pre-junctional effects on nerve fibres within the muscularis externa. 4 Inhibition of junction potentials by MetEnk and DADLE was blocked by approximately the same extent by naloxone (106 M) and ICI 174,864 (106M), a 6-specific antagonist. 5 MetEnk and DADLE blocked a portion of the ij.p. that was sensitive to arginine analogues; after treatment with N0-nitro-L-arginine methyl ester (L-NAME, 10-4 M), MetEnk and DADLE had no further effect on i.j.ps. These data suggest that opioids regulate nitric oxide-dependent neurotransmission.6 Naloxone (10-6 M) alone had no effect on ij.ps elicited by short trains of electrical field stimuli. 7 Ij.p. amplitude was reduced after a period of conditioning stimulation (2 min, 30 Hz, 30 V). Naloxone blocked the post-stimulation inhibition. Repetitive stimulation at high frequencies (30 Hz) resulted in sustained hyperpolarization. Naloxone increased the amplitude of the hyperpolarization responses elicited by high frequency stimulation. 8 These results show that ej.ps and ij.ps in the canine pylorus are inhibited by opioids. A portion of the inhibitory effects appears to be mediated via 6 receptors. 9 Although pyloric muscles are richly innervated by nerves containing opioid peptides, brief trains of stimuli do not appear to release concentrations of opioids that are effective in regulating junction potentials. Higher frequency stimulation (or longer durations of stimulation) appear to be necessary to release concentrations of opioids that are effective in modulating the amplitude of junction potentials.

Localization and Regulation of Fluorescently Labeled Delta Opioid Receptor, Expressed in Enteric Neurons of Mice

“…The effects of enkephalins on inhibitory junction potentials in the dog duodenum are neurogenic and DOR-dependent 9 , suggesting that opioids activate DOR on inhibitory motoneurons that control neuromuscular transmission to circular muscle. The effects of opioids on inhibitory junction potentials are retained in preparations devoid of the myenteric plexus, supporting an action at inhibitory motor nerves within the circular muscle or deep muscular plexus 9, 33 .…”

Rapid tolerance to morphine in the myenteric neurons of the small intestine is independent of β-arrestin-2 and mediated by PKC

“…Notably, in this experiment, basal small intestinal transit of morphinepelleted animals was reduced leading to the perception of incomplete tolerance. This is likely due to opioid-induced increase in sphincter tone resulting in delayed gastric emptying (Bayguinov and Sanders, 1993;Holzer, 2009). Furthermore, morphine tolerance to whole GI transit is incomplete, implicating the colon in chronic opioid-induced constipation.…”

Duodenogastric reflux following cholecystectomy in the dog: role of antroduodenal motor function

“… 22 Bayguinov et al . have reported that exogenous opioids specifically reduce the nitric oxide‐dependent inhibitory junction potentials via δ opioid receptors in the circular muscle layer of the canine pyloric sphincter 23 . Trimebutine has been shown to interact with δ opioid receptors 16 , .…”