L.A. Morrone

Manifestations of acute opiate withdrawal contracture in rabbit jejunum after μ‐, κ‐ and δ‐receptor agonist exposure

1 Following a 5 min in vitro exposure to morphine (1.3 × 10−7 m), U‐50,488H (2.5 × 10−8 m) and deltorphin (1.6 × 10−8 − 6.5 × 10−9 m), the rabbit isolated jejunum exhibited a precipitated contracture after the addition of naloxone (2.75 × 10−7 m). 2 The precipitated responses to U‐50,488H and deltorphin but not to morphine were reproducible in the same tissue. 3 The precipitated contractures were blocked completely by tetrodotoxin (3 × 10−7 m), partially by atropine (1.5 × 10−7 m) and not affected by hexamethonium (1.4 × 10−5 m). 4 Naloxone administration (2.75 × 10−7 m) before the agonist prevented the development of the adaptive response to morphine and U‐50,488H but not to deltorphin. 5 The selective antagonists norbinaltorphimine (2.7 × 10−8 − 2.7 × 10−9 m) and naltrindole (1.1 × 10−7 m) prevented the adaptive response development only to the respective agonists. 6 The opioid agonists partially inhibited the spontaneous activity of the tissue. This study has shown that independent activation of μ‐, κ‐ and δ‐opioid receptors can induce dependence in this isolated tissue. Rabbit jejunum is a suitable tissue for studying the acute effects of opioids on the adaptative processes determined by their administration.

Some pharmacological characteristics of the guinea pig ileum opioid system activated by cholecystokinin

Naloxone, added after contractions induced by CCK-8 on the guinea pig ileum preparation, elicited a contraction attributed to the release of endogenous opioid which could inhibit the excitatory action of the peptide. With large concentrations of CCK-8, the preparation gave reproducible responses with time. Naloxone, added before the peptide, protracted the excitatory response to CCK-8, but not its height. Morphine decreased the response to CCK-8 but simultaneously raised the response to naloxone. The latter effect appeared very similar to the withdrawal contraction observed after brief exposure of the opioid in the guinea pig ileum to opioids. Clonidine, and alpha-2 adrenoceptor agonist, and nifedipine, a calcium channel antagonist, both known to interfere with tolerance and physical dependence, affected the excitatory response to CCK-8 and the subsequent response to naloxone in a different way.

Ocular absorption and distribution of bendazac after topical administration to rabbits with different vehicles

Ocular and systemic absorption of bendazac was investigated after topical administration to rabbits of 0.5% solutions of bendazac lysine in different polysaccharide vehicles. The results show that the drug is absorbed into the retina-choroid via an extracorneal, or sclero-conjunctival route; the iris and the ciliary body are presumably supplied via both the transcorneal and the extracorneal pathways. The extent of absorption via the extracorneal route is not related to vehicle viscosity but rather to the chemical features of vehicle. The transcorneal penetration appears to be hindered by the binding of the drug to corneal tissues.

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.

Dapiprazole, a selective alpha-1 adrenoceptor antagonist, inhibits diuresis but not polydipsia produced by amphetamine in rats

Chronic amphetamine administration has been found to produce diuresis and polydipsia in rats. We have found that dapiprazole acutely suppresses the diuretic, but not the ingestive, effects of amphetamine. To see whether diuresis is the physiological stimulus driving amphetamine-mediated polydipsia, we injected rats daily with d,l-amphetamine and the alpha-1 adrenergic antagonist dapiprazole. Throughout 19 days of treatment, dapiprazole completely prevented the increased urine output produced by amphetamine, but did not affect the development of polydipsia. This finding rules out a renal site of the primary action for amphetamine-mediated polydipsia and proposes water and electrolyte imbalance produced by chronic amphetamine administration as a model of the polydipsia and hyponatremia that develop in some psychotic patients.

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.

Effects of trazodone and m-chlorophenylpiperazine (m-CPP) on acute dependence in mice

The antidepressant trazodone and its main metabolite, m-CPP, having an antiserotoninergic and serotoninergic activity respectively, were studied in an acute dependence model in mice, to establish whether 5-hydroxytryptaminergic systems are involved in the manifestations of acute opiate dependence and in its development. When drugs were administered 15 min before naloxone, all signs of abstinence decreased, with the exception of teeth chattering that was increased by m-CPP and unaffected by trazodone. When injected 15 min before morphine, jump episodes were decreased by the highest doses of both drugs, while teeth chattering was decreased by m-CPP only. When administered 1 h before morphine, trazodone increased paw and head shakes and mCPP decreased teeth chattering and both left the other signs unaffected. Serotoninergic systems seem to have a significant role in events involved in the withdrawal syndrome and a minor one in those leading to the development of dependence.