[Met⁵]enkephalin acts via δ‐opioid receptors to inhibit pelvic nerve‐evoked contractions of cat distal colon

Abstract

The effects of opioids on the sacral parasympathetic outflow to cat distal colon were studied in vitro using muscle strips orientated in the axis of the longitudinal muscle layer, with pelvic nerves attached. Electrical stimulation of the pelvic nerves evoked contractions that were blocked by atropine (1 × 10−6 m) and tetrodotoxin (3 × 10−7 m). [d‐Pen2, d‐Pen5]enkephalin and [Met5]‐ and [Leu5]enkephalin caused concentration‐dependent, reversible inhibition of pelvic nerve‐evoked contractions, with IC50 values of 8.3 × 10−10 m, 2.2 × 10−9 m and 2.1 × 10−9 m respectively. Morphine (1 × 10−7‐1 × 10−5 m) and [d‐Ala2, MePhe4, Gly‐ol5]enkephalin (1 × 10−8‐1 × 10−6 m) and U‐50,488H (1 × 10−8‐1 × 10−6 m) were much less potent as inhibitors than [Met5]‐ or [Leu5]enke‐phalin. Naloxone (1 × 10−7 m), an antagonist at each of the three opioid receptor types, antagonized the effects of both [Met5]enkephalin and morphine. However, ICI 174,864, a specific δ‐opioid receptor antagonist, antagonised the effects of [Met5]enkephalin only. The inhibitory actions of [Met5]enkephalin were inversely related to frequency of pelvic nerve stimulation. Also, [Met5]enkephalin at a concentration (3 × 10−9 m) which produced a large inhibition of neurogenic contractions, had no effect on contractions to exogenous acetylcholine. These results suggest a prejunctional site for inhibitory opioid receptors. In summary, prejunctional inhibitory δ‐opioid receptors are present on the sacral parasympathetic outflow to cat distal colon; κ‐and/or μ‐opioid receptors may also be present, but appear to be of lesser importance.

Enkephalins modulate inhibitory neuromuscular transmission in circular muscle of human colon via delta‐opioid receptors.

“…dynorphin A or ,J-endorphin, and several times more potent than DAMGE (McKnight, Corbett, Marcoli & Kosterlitz, 1985;Takemori & Portoghese, 1985;von Kiugelgen, Illes, Wolfe & Starke, 1985;Sheehan, Hayes & Tyers, 1986;Kennedy & Krier, 1987) endorphin and DAMGE in the human colon imply that the actions of LENK and MENK are predominantly or solely mediated by o-opioid receptors. The site of action of LENK and MENK and the synthetic enkephalins is most likely to be prejunctional.…”

δ‐Opioid receptors mediate inhibition of fast excitatory postsynaptic potentials in cat parasympathetic colonic ganglia

“…Effects of naloxone and ICI 174,864 Naloxone (106 M) and ICI 174,864 (10-6 M) (a selective antagonist at 6-opioid receptors (Cotton et al, 1984;Corbett et al, 1984;Kennedy & Krier, 1987a)) had no effect on transmembrane potential or membrane input resistance (n = 5 and n = 3, respectively In the presence of naloxone (10-6 M), the inhibitory actions of DPDPE (3 x 10-6 M-6 M) on fast e.p.s.ps were significantly antagonized (P < 0.05) (Figure 3a) (control =44± 4% inhibition: test 6± 6% inhibition: n = 3 in both cases). This was seen whether naloxone had potentiated fast e.p.s.ps (n = 1) or not (n = 2).…”

“…In a previous study we showed that opioids inhibit pelvic nerve-evoked contractions of cat distal colon longitudinal muscle in vitro (Kennedy & Krier, 1987a). This action was mediated via prejunctional 6-opioid receptors, located, at least in part, on neurones in the colonic myenteric plexus.…”

“…The 6-selective agonist, DPDPE (Mosberg et al, 1983;Corbett et al, 1984), inhibited fast e.p.s.ps (and could abolish them at the highest concentration), whereas the K-selective agonist, U-50,488H (Piercy et al, 1982) and the L-selective agonist, [D-Ala2, MePhe4, Gly-ol5) enkephalin (Handa et al, 1981;Cotton et al, 1984) had little or no effect. Furthermore, the inhibitory actions ofDPDPE were largely inhibited by naloxone and abolished by ICI 174,864, a 6-selective antagonist (Cotton et al, .984;Corbett et al, 1984;Kennedy & Krier, 1987a).…”

“…6-Opioid receptors have also been shown to be present in other neurones of the gastrointestinal tract, including guinea-pig caecum submucous plexus (Mihara & North, 1986) and cat colonic myenteric plexus (Kennedy & Krier, 1987a). 6-Opioid receptors have also been suggested to mediate inhibition of neurotransmission in other parasympathetic (Simonds et al, 1983;Katayama & Nishi, 1984) and sympathetic (Konishi et al, 1979; ganglia and of action potentials of neurones in sensory ganglia (Werz & McDonald, 1983), though this awaits confirmation with selective agonists and antagonists.…”