L. Romanelli

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.

Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro

The hallucinogenic effects of lysergic acid diethylamide (LSD) have mainly been attributed to the interaction of this drug with the serotoninergic system, but it seems more likely that they are the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems. The aim of the present study was to investigate the functional actions of LSD at dopaminergic receptors using prolactin secretion by primary cultures of rat pituitary cells as a model. LSD produced a dose-dependent inhibition of prolactin secretion in vitro with an IC50 at 1.7x10(-9) M. This action was antagonized by spiperone but not by SKF83566 or cyproheptadine, which indicates that LSD has a specific effect on D2 dopaminergic receptors. The maximum inhibition of prolactin secretion achieved by LSD was lower than that by dopamine (60% versus 80%). Moreover, the fact that LSD at 10(-8)-10(-6) M antagonized the inhibitory effect of dopamine (10(-7) M) and bromocriptine (10(-11) M) suggests that LSD acts as a partial agonist at D2 receptors on lactotrophs in vitro. Interestingly, LSD at 10(-13)-10(-10) M, the concentrations which are 10-1000-fold lower than those required to induce direct inhibition on pituitary prolactin secretion, potentiated the dopamine (10(-10)-2.5x10(-9) M)-mediated prolactin secretion by pituitary cells in vitro. These results suggest that LSD not only interacts with dopaminergic receptors but also has a unique capacity for modulating dopaminergic transmission. These findings may offer new insights into the hallucinogenic effect of LSD.

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.

Interactions between prebiotics, probiotics, polyunsaturated fatty acids and polyphenols: diet or supplementation for metabolic syndrome prevention?

Abstract The metabolic syndrome can be prevented by the Mediterranean diet, characterized by fiber, omega-3 polyunsaturated fatty acids and polyphenols. However, the composition of the Mediterranean diet, which can be viewed as a natural multiple supplement, is poorly controlled, and its beneficial effects poorly predictable. The metabolic syndrome is associated with intestinal dysbiosis and the gut microbioma seems to be the main target and player in the interactions occurring between probiotics, prebiotics, omega 3 polyunsaturated fatty acids, and polyphenols. From the reviewed evidence, it is reasonable to manage growth and metabolism of gut microflora with specific prebiotics and polyphenols. Even though the healthy properties of functional foods and nutraceuticals still need to be fully elucidated, available data suggest that well-designed supplements, containing the better ratio of omega-3 polyunsaturated fatty acids and antioxidants, specific probiotic strains, and selected polyphenols and prebiotics, could be useful in metabolic syndrome prevention and treatment.

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.

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.

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.

Acute withdrawal induced by adenosine A1‐receptor activation in isolated guinea‐pig ileum: role of opioid receptors and effect of cholecystokinin

Objectives In isolated guinea‐pig ileum, the μ‐opioid acute withdrawal response is under control of several neuronal systems, including the κ‐opioid and the A1‐adenosine systems, which are involved in the μ‐withdrawal response inhibitory control. After μ‐opioid system stimulation, indirect activation of both κ‐opioid and A1‐adenosine systems is prevented by the peptide cholecystokinin‐8 (CCk‐8). Guinea‐pig ileum exposed to A1‐adenosine agonist (CPA), shows a withdrawal contracture precipitated by the A1‐adenosine antagonist (CPT). We investigated this response.