Involvement of κ‐opioid receptors in peripheral response to nerve stimulation in κ‐opioid receptor knockout mice

Abstract

1 The present study aimed to evaluate the role of kappa-opioid receptors at two peripheral sites, the vas deferens and the proximal colon, in kappa-opioid receptor knockout mice. We investigated the role of the kappa-opioid receptor in the vas deferens twitch response and in the colonic "off-contraction", a rebound contractile response which follows the inhibitory response to low frequencies stimulation (10, 20, 30 Hz) and which has been suggested to "locally" reproduce the contractile component of the peristaltic reflex. 2 Transmural stimulation of the vas deferens at lower frequencies (10 Hz, 10 V, 1 ms pulse trains lasting 0.5 s) evoked a contractile response that was significantly higher in the preparations from knockout mice because of lack of kappa-opioid receptors than in wild type mice. A selective kappa-opioid receptor agonist, U-50,488H, induced a dose-dependent inhibition of the electrically stimulated contraction in vas deferens. The percentages of reduction of the twitch response were significantly lower in knockout mice than in wild type mice after treatment with U-50,488H. The reduction of twitch response caused by U-50,488H was not reversed by administration of nor-binaltorphimine (nor-BNI) (5 x 10-6 m), a selective kappa-opioid receptor antagonist, in preparations from both knockout mice and wild type mice. U-50,488H has no effect on postsynaptic adrenergic receptors, as its administration did not affect the direct contractile response to noradrenaline. 3 Transmural stimulation (5 Hz, 20 V, 2 ms pulse trains lasting 30 s) induced inhibition of spontaneous activity of colonic strips during the period of stimulation, followed by an "off-contraction" after the cessation of stimulation. The statistical evaluation of the "off-contraction" responses between the two strains showed no significant difference. The off-contraction, measured in specimens from knockout mice, was inhibited concentration-dependently by U-50,488H (P < 0.01) and significantly less than from wild type mice. 4 The effect of U-50,488H was not reversed by administration of nor-BNI (5 x 10-6 m), either in preparations from knockout mice or from wild type mice. 5 Our data may suggest that kappa-opioid receptors are involved in some peripheral responses to the nerve stimulation, as indicated by the effect of U-50,488H, a selective kappa-opioid receptor agonist. However, the involvement of kappa-opioid receptor was also present, although less apparent, in kappa -opioid receptor knockout mice, suggesting either that this drug acts not only on kappa-opioid receptors but also on other receptor sites, such as kappa-like receptors. An alternative interpretation can be related to a sodium channel blocking action of U-50,488H, which could explain the inhibitory effects of twitch response still present but less evident in knockout strain and the lack of effect of the antagonist nor-BNI.

Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications

“…However, these findings are compromised by the lack of specific and reliable antibodies and are yet to be replicated using other technologies. It has been suggested that KOR agonists modulate nonadrenergic noncholinergic mediated "rebound" contractile responses in enteric smooth muscle, but genetic deletion of KOR had no effect on the physiology of these responses (78). Furthermore, the inhibitory effects that the widely used KOR agonist U50-488H has on this system are not blocked by selective KOR antagonism with nor-binaltorphimine, suggesting off-target effects (78).…”

The effect of opioids on gastrointestinal function in the ICU

“…MOR and DOR are both distributed in the submucosal plexus and myenteric plexus, and the activation of MOR and DOR suppresses the excitation of enteric neurons by hyperpolarizing them, delays gastric emptying, increases the time of gastrointestinal transit, and suppresses the secretion of water and electrolytes in the intestine. The activation of KOR also inhibits the ENS contractile response, but its inhibition of the GI tract is weaker than that of MOR and DOR [ 30 , 31 ].…”

Opioid-Induced Gastrointestinal Dysfunction

“…But the observations from these studies refl ect the pharmacological effects of endogenous opioids rather than their physiological functions. Use of knockout mice models for opioid receptors in evaluating the physiological role of endogenous opioid peptides in gastrointestinal function is only beginning [81,82] .…”