The present study was undertaken to investigate firstly whether a brief exposure for 5 min of guinea‐pig isolated ileum to the κ‐opioid agonist, U‐50,488H produced a withdrawal contracture on addition of naloxone and secondly to ascertain whether the response was due to the activation of κ‐opioid receptors. Naloxone (10−6 m) did not elicit a response in preparations exposed to U‐50,488H (5 × 10−7 M‐2 × 10−6 m). However, after exposure to U‐50,488H (5 × 10−7 m), naloxone (10−6 m) produced a strong contracture if the agonist was washed out 1 min before the addition of the antagonist. The addition of naloxone (10−6 m) to the ileum preparation exposed to U‐50,488H (10−7 m or lower) caused a response of similar intensity irrespective of whether the agonist had been washed out. The selective κ‐opioid antagonist, nor‐binaltorphimine (2.7 × 10−9 m and 2.7 × 10−7 m), injected before the opioid agonists, prevented the naloxone‐induced contracture after exposure to U‐50,488H (8 × 10−8 m) but did not affect the contracture after exposure to morphine (5 × 10−7 m). Nor‐binaltorphimine (2.7 × 10−9 m) caused a contraction of the ileum preparation when injected min after exposure to U‐50,488H (8 × 10−8 m) but not after morphine (5 × 10−7 m). The α2‐adrenoceptor agonist, clonidine (3 × 10−8 m) and the calcium channel blocker, nifedipine (3 × 10−8 m), injected 1 min before naloxone, blocked the ileum contraction to naloxone after exposure to U‐50,488H (8 × 10−8 m). The results demonstrate that the stimulation of K‐opioid receptors can induce a similar dependence in guinea‐pig ileum to that produced by activation of μ receptors.

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1 Although cholecystokinin octapeptide sulphate (CCK-8) activates the opioid system of isolated guinea-pig ileum (GPI) whether it activates the m-or k-system, or both, remains unclear. Neither is it known whether CCK-8 in¯uences the withdrawal responses in GPI preparations brie¯y exposed to opioid agonists. This study was designed to clarify whether CCK-8 activates m-or k-opioid systems or both; and to investigate its eect on the withdrawal contractures in GPI exposed to m-or kagonists and on the development of tolerance to the withdrawal response. 2 In GPI exposed to CCK-8, the selective k-antagonist nor-binaltorphimine elicited contractile responses that were concentration-related to CCK-8 whereas the selective m-antagonist cyprodime did not. 3 In GPI preparations brie¯y exposed to the selective m-agonist, dermorphin, or the selective kagonist, U-50, 488H, and then challenged with naloxone, CCK-8 strongly enhanced the withdrawal contractures. 4 During repeated opioid agonist/CCK-8/opioid antagonist tests tolerance to opioid-induced withdrawal responses did not develop. 5 These results show that CCK-8 preferentially activates the GPI k-opioid system and antagonizes the mechanism(s) that control the expression of acute dependence in the GPI.

1. One reason why rabbit jejunum is suitable for studying the mechanisms underlying the actions of the various neurotransmitters and their interactions is its spontaneous motility. The main regulator of spontaneous motility is the cholinergic system. How the cholinergic system regulates the spontaneous activity in the rabbit jejunum and how it affects the inhibitory action of alpha- and beta-adrenoceptor agonists remains unclear. 2. We studied the influence of the cholinergic system and apamin-sensitive Ca2+-activated K+ channels on spontaneous contractions in the rabbit jejunum and on the inhibitory effects of alpha1- and beta-adrenoceptor agonists. 3. In naïve tissues, atropine (ATR, 7.4 x 10(-8) m) and tetrodotoxin (8 x 10(-8) m) almost completely inhibited - to a similar extent - the amplitude of spontaneous activity. Despite the presence of ATR or TDX, tissue contraction gradually recovered to about 50% of the baseline amplitude within 5-10 min. When ATR or TDX, respectively, were added to the TDX- or ATR-treated tissues, the recovered activity decreased weakly but significantly. After washout and a 45-min rest the contraction amplitude returned to baseline values. A further exposure to ATR or TDX reduced the contraction to a level significantly lower than the one obtained after TDX or ATR added 5 min after ATR or TDX, respectively. In preparations prestimulated for 10 min with acetylcholine (ACh), ATR abolished the TDX-resistant recovered spontaneous activity. 4. Adrenaline (ADR, 0.5-5 x 10(-7) m) and phenylephrine (PHE, 1-10 x 10(-7) m) inhibited tissue motility in naïve and in ATR- and in TDX-exposed preparations. But whereas in naïve preparations the alpha1-adrenoceptor antagonists completely antagonized inhibition induced by both drugs, in ATR- and TDX-exposed tissues they did so only partially for ADR. Agonist-induced inhibition had a rapid onset but rapidly faded; pendular movements took significantly longer to recover in ATR- and TDX-treated tissues than in naïve tissues. In tissues exposed for 2 min to ADR (0.5-5 x 10(-7) m) or PHE (1-10 x 10(-7) m), washout or addition of alpha1-adrenoceptor antagonists caused an immediate short-lasting increase in contraction amplitude. 5. Apamin (APAM, 5 x 10(-9) m) caused a rapid and persistent increase in the amplitude of contractions. It also blocked the inhibitory responses to ADR and PHE, and removed washout-induced contractions. The APAM-induced increase in the contraction amplitude correlated with the increase obtained by washing out ADR or PHE. 6. Isoprenaline (at concentrations up to 2.8 x 10(-7) m) produced no inhibitory response in naïve tissues, but it invariably blocked (at a concentration of 0.7 x 10(-7) m) the recovered spontaneous activity (and sometimes depressed muscletone) in tissues exposed to ATR or TDX. Neither propranolol (3.4 x 10(-7) m) nor APAM (5 x 10(-9) m) counteracted these inhibitory effects. 7. These results indicate that spontaneous motility in the rabbit jejunum is predominantly mediated by neuronal release of ACh and by some oth...