M.J. Alfaro

Age-related changes in nociception, behavior, and monoamine levels in rats.

1. Pain threshold, behavioral parameters, and monoamine levels were compared in two groups of rats: adult (12 months old) and old rats (25 months old). 2. No differences in nociception were found between the two groups using the tail-shock test. 3. Behavioral experiments with the holeboard test showed that locomotor activity and exploration activity were lower in aged animals, whereas no significant differences were found in emotivity. 4. Using high-performance liquid chromatography (HPLC) techniques, we found that serotonin and dopamine showed lower levels in the old group.

Effect of Bay K 8644 on the synthesis and metabolism of dopamine and 5‐hydroxytryptamine in various brain areas of the rat

Abstract— The effects of Bay K 8644 (1,2 and 4 mg kg−1, i.p.) on the synthesis and metabolism of dopamine and 5‐hydroxytryptamine (5‐HT) in rat brain after m‐hydroxybenzylhydrazine administration were studied. Bay K 8644 (2 and 4 mg kg−1, i.p.) caused an increase in the synthesis of both dopamine in the striatum and 5‐HT in the midbrain and striatum, measured as the accumulation of 3,4‐dihydroxyphenylalanine (dopa) and 5‐hydroxytryptophan, respectively. Moreover, Bay K 8644 at the dose of 4 mg kg−1 increased the turnover of dopamine in the striatum and of 5‐HT in midbrain and striatum. These neurochemical changes were antagonized by the calcium channel antagonist nimodipine (10 mg kg−1, i.p.). It is concluded that dihydropyridine receptors may mediate the brain region‐specific changes in the dopaminergic and 5‐HT‐ergic neurotransmission which occur following activation of neuronal calcium channels.

In vitro study of the interaction of salmon calcitonin with μ, δ and κ opioid agonists

SummaryA possible interaction of salmon-calcitonin with opioid systems was studied in isolated tissues. Neurogenic contractions were elicited by electrical stimulation in guinea-pig ileum myenteric plexus-longitudinal muscle strips, rabbit vas deferens and mouse vas deferens.Bremazocine inhibited neurogenic contractions in all three tissues (presumably through κ-receptors) [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin inhibited contractions in mouse vas deferens (presumably through δ-receptors), and [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) inhibited contractions in guinea-pig ileum and mouse vas deferens (presumably through μ-receptors). All inhibitory effects were concentration-dependent. Salmon-calcitonin 0.1 IU/ml increased the effect of bremazocine in guinea-pig ileum and rabbit vas deferens and also increased the effects of [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin in mouse vas deferens. In contrast, salmon-calcitonin up to 0.4 IU/ml did not change the effect of bremazocine in mouse vas deferens and the effect of DAMGO in guinea-pig ileum and mouse vas deferens.It is concluded that salmon-calcitonin enhances agonist effects at opioid κ- and δ- but not at opioid μ-receptors. The level of this interaction remains to be elucidated. The interaction may be the basis of the analgesic effect of salmon-calcitonin in vivo.

Effect of nimodipine, diltiazem and BAY K 8644 on the behavioural and neurochemical changes associated with naloxone-precipitated withdrawal in the rat. A comparison with clonidine

1. Nimodipine, diltiazem and BAY K 8644 decreased the incidence of wet dog shakes, teeth chattering, grooming and diarrhoea to a similar degree of clonidine. 2. Nimodipine, diltiazem and BAY K 8644 had no effect on changes in the serotonin metabolism induced by naloxone precipitated abstinence syndrome. 3. Clonidine decreased the ratio of serotonin turnover in the brain of morphine-dependent rats. 4. From these experiments it is concluded that nimodipine, diltiazem and BAY K 8644 exert their effects in preventing morphine withdrawal symptoms through a mechanism independent of the serotonergic system.

Behavioral and analgesic effects induced by administration of nifedipine and nimodipine.

Evidence exists that calcium antagonists can have effects on neural function. The aim of this work is to analyze the effect of two dihydropyridines, nifedipine and nimodipine, administered for 11 days on the behavior and pain sensitivity of rats. Nociception was tested using the tail electric stimulation test, and behavior parameters using a holeboard. Our results show that chronic administration of nifedipine or nimodipine induces analgesia that can be evaluated by tail withdrawal. However, neither the vocalization nor the vocalization after discharge were modified, so the analgesia may be mediated by spinal mechanisms. Rats treated with nifedipine or nimodipine exhibited a dose-dependent tendency to avoid the center of the field without modification of other parameters, suggesting an increased emotivity in the rats. This conclusion is supported by the fact that anxiogenic or anxiolytic drugs modify the pattern of locomotion without significant changes in other parameters related with the motility. The results from this study suggest the view of a complex mechanism of action underlying nifedipine- and nimodipine-mediated behavioral effects.

Analgesic effect of two calcitonins and in vitro interaction with opioids

1. When the analgesic effect of salmon-calcitonin (S-CT) and of eel-calcitonin (E-CT), as well as their influence on the morphine-analgesia were compared, no significant differences were found. 2. While on isolated tissues, E-CT induced a significant increase on the effect of bremazocine, [D-Pen2,D-Pen5]enkephalin and [Met5]enkephalin and no changes were observed on the effect of DAMGO, suggesting that E-CT increases the effects of opioids acting on delta or kappa receptors but not on mu receptors. 3. These findings corroborate the possibility of interactions between calcitonin and the opioid system.

Effect of salmon-calcitonin on the analgesic effect of selective μ, δ and κ opioid agonists in mice

Abstract The analgesic effect of three different opioid agonists, DAMGO ([ d -Ala 2 , N -Me-Phe 4 ,Gly 5 -ol]enkephalin), U-50,488H ( trans -3,4-dichloro- N -methyl- N -[2-(1-pyrrolidynyl)cyclohexyl] benzene-aceramide methane sulphonate), and [ d ,Pen 2 - d ,Pen 5 ]-enkephalin, which act upon μ , δ and κ opioid receptors, respectively, was compared in the presence and absence of salmon-calcitonin (s-CT). The analgesic test used was the writhing test in mice. The analgesic effect of the opioids was significantly enhanced by pretreatment of the animals with s-CT intraperitoneally (i.p.) administered. This effect was more evident for the δ and κ -agonists. The present result suggests that the joint administration of s-CT and opioids may be a useful and interesting alternative in the treatment of painful diseases resistant to other treatments.

The effect of dihydropyridine calcium channel agents on 5‐HT metabolism in the CNS of the rat

Abstract— The effects of dihydropyridines on the levels of 5‐hydroxytryptamine (5‐HT) and 5‐hydroxy‐3‐indole acetic acid (5‐HIAA) in the spinal cord and various brain regions of the rat have been studied. Nimodipine, nitrendipine and nifedipine (10 mg kg−1), nisoldipine (5 mg kg−1), and BAY K8644 (0–2 and 2 mg kg−1) were administered i.p. 1 h before killing. The administration of nifedipine and nitrendipine increased 5‐HT turnover in all of the areas studied except for the spinal cord. Nisoldipine increased 5‐HT turnover in midbrain, hippocampus and cortex, while the effect of nimodipine was restricted to midbrain. BAY K8644 at 2 mg kg−1 produced the same effects as nifedipine and nitrendipine; however, at low doses (0·2 mg kg−1), this compound increased 5‐HT turnover only in midbrain and medulla oblongata. These results indicate that both dihydropyridine calcium channel agonist and antagonists are able to activate the 5‐HT‐ergic system in the central nervous system of the rat in‐vivo. Therefore, it seems likely that such effects could be due to indirect actions or to interactions of the compounds with receptors other than the voltage‐sensitive calcium channels.

Influence of pertussis toxin on the calcitonin-opioid interaction in isolated tissues.

1 In order to clarify one of the mechanisms involved in the analgesic effect of calcitonin, we have tested the in vitro modifications induced by calcitonin on the effect of opioids. 2 The inhibition of the contractions induced by opioids or clonidine, in guinea‐pig ileum or in mouse vas deferens, were significantly reduced in tissues incubated with pertussis toxin (PTX). When tissues were incubated with PTX and calcitonin, the inhibitory effect was restored. 3 These results suggest that calcitonin is able to potentiate a non‐PTX‐sensitive mechanism of transduction and support the possibility of involvement of similar G‐proteins in the effects of opioid and α2‐adrenoceptor agonists.

Dihydropyridines on guinea-pig ileum

1. The effects of three dihydropyridine derivates were studied and compared with those of nifedipine in guinea-pig ileum. 2. Nifedipine, nimodipine, nitrendipine (25-200 nM) and nisoldipine (10-80 nM) produced a dose-dependent inhibition of the contractile responses induced by single pulse stimulation, acetylcholine (1 microM) and high-K (50 mM). 3. From these experiments it is concluded that nimodipine and nitrendipine, like nifedipine, produced a similar and potent inhibitory effect of the contractile responses induced in the guinea-pig ileum. 4. Nisoldipine resulted to be the most active agent.