P. Valeri

Reproducible withdrawal contractions of isolated guinea-pig ileum after brief morphine exposure : effects of clonidine and nifedipine

Abstract— Guinea‐pig ileum stored for 30 min in Krebs solution and then mounted in Tyrode solution gave reproducible contracture responses to naloxone after brief exposure to morphine. The preparation lasted for several hours and a variety of pharmacological tests could be made. Clonidine, an α2‐adrenoceptor agonist, and nifedipine, a calcium channel antagonist, both known to interfere with tolerance and physical dependence, inhibited naloxone withdrawal contractures in a dose related way. Their action seemed to be receptor‐mediated since yohimbine and Bay k 8644, respectively, reversed their inhibitory effect.

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.

Dissociation in the effects of the D2/D3 dopaminergic agonist quinpirole on drinking and on vasopressin levels in the rat

In the present study, we investigated the role of vasopressin in the development of quinpirole-induced hyperdipsia in the rat. We report that: (1), an acute intraperitoneal (i.p.) injection of 0.56 mg/kg of quinpirole increased plasma vasopressin (radioimmunoassay) at 15 min but not at 30 or 120 min; (2), nine daily injections of quinpirole (0.56 mg/kg, i.p.) progressively increased water intake and diuresis for a period of several hours after each treatment; (3), quinpirole hyperdipsia was associated with apparently normal levels of vasopressin (which might be considered inappropriately high in the presence of excessive drinking); (4), quinpirole reduced vasopressin and oxytocin, but not angiotensin, immunoreactivity in the supraoptic nucleus. These findings suggest that quinpirole hyperdipsia is a sound animal model of psychotic polydipsia.

Specific [3H]corticosterone uptake in the hippocampus and septum varies with social settings in mice: Hormone-receptor autoregulation may be involved

Specific [(3)H]corticosterone uptake in hippocampus and septum was reduced in socially deprived, as well as in crowding-stressed mice, in comparison with grouped ones. Its magnitude was related to hierarchic rank in the group but unrelated to agressiveness which, in turn, was unaffected by adrenalectomy and corticosterone replacement. A complex, regulatory interplay may exist between limbic specific corticosterone receptors and hypophyso-adrenal activity.

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.

Ocular distribution of aspirin and salicylate following systematic administration of aspirin to rabbits

Abstract— The distribution of aspirin and salicylate 30 min after the intravenous administration of different doses of aspirin has been investigated in the rabbit eye. HPLC enabled a rapid and sensitive determination of both substances. A considerable dose‐dependent penetration into all ocular tissues was observed with both aspirin and salicylate. Aspirin concentrations were higher than in plasma in all ocular tissues with the exception of the lens. These results show that an unhydrolysed drug may have a direct local effect by acetylating lens protein or other ocular constituents.

Ocular pharmacokinetics of dapiprazole

Dapiprazole is a drug having specific alpha 1 adrenergic blocking properties. Following topical instillation on the eye, it crosses the corneal epithelium reaching high concentrations in the ocular tissue and producing a prompt miotic and hypotensive effect. The high concentration ratio between ciliary bodies and iris versus aqueous humor suggests a peculiar affinity for these structures containing adrenoceptors of the alpha type. The very low concentrations in the plasma, as compared to those after systemic administration, and in the fellow eye indicate that the systemic absorption is negligible.