M.C. Amico

Withdrawal contractures of guinea‐pig isolated ileum after acute activation of κ‐opioid receptors

1 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. 2 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. 3 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. 4 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). 5 Nor‐binaltorphimine (2.7 × 10−9 m) caused a contraction of the ileum preparation when injected 5 min after exposure to U‐50,488H (8 × 10−8 m) but not after morphine (5 × 10−7 m). 6 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.

Acute withdrawal after bremazocine and the interaction between μ- and κ-opioid receptors in isolated gut tissues

1 This study was undertaken to investigate whether, after a brief exposure of guinea‐pig isolated ileum and rabbit jejunum to bremazocine, a κ‐opioid agonist also possessing antagonist activity at μ‐opioid receptors, the addition of opioid antagonists produced withdrawal contractures. Our aim was to verify in these tissues the existence of an interaction between the μ‐ and κ‐opioid systems.

Mu and kappa opioid system interactions in the expression of acute opioid dependence in isolated guinea-pig ileum.

In vivo studies have suggested that the kappa opioid system can partially inhibit the development of physical dependence to mu agonists. Vice versa, activation of mu receptors may inhibit the expression of physical dependence to kappa agonists. We studied mu-kappa interactions in the isolated guinea-pig ileum (GPI). In the isolated GPI briefly exposed to mu or kappa agonists the addition of the respective antagonists precipitated a withdrawal contracture. After a first withdrawal response, however, some tissues failed to exhibit subsequent mu or kappa withdrawal contractures. A withdrawal contracture to the selective mu antagonist, cyprodime, after repeated exposures to a selective mu agonist, dermorphin, was restored by nor-binaltorphimine (BNI), a selective kappa antagonist. Vice versa, after repeated exposures to the kappa agonist, U-50,488H, cyprodime restored tissue responsiveness to BNI. Tissues repeatedly exposed to dermorphin and washed after each exposure contracted to the addition of BNI. Tissues repeatedly exposed to U-50,488H contracted on the addition of cyprodime. These findings strongly suggest that exogenous agonist-elicited stimulation of the mu (or kappa) opioid system indirectly activates the endogenous kappa (or mu) system. The indirectly-activated endogenous system inhibits the withdrawal response to the exogenously-stimulated opioid system. In isolated GPI the mu and kappa opioid systems thus appear to interact, regulating each other.