M.I. Serrano

Implication of β1- and β2-adrenergic receptors in the antinociceptive effect of tricyclic antidepressants

Abstract Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective β 1 - (CGP 20712A) and β 2 - (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect “false positive” or “false negative” results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by β-adrenoceptors. The β-adrenoceptor involved depends on the type of nociceptive stimulus: β 1 and β 2 are both implicated when the stimulus is physical, but only β 1 is involved when the stimulus is chemical.

Behavioral Expression of Opiate Withdrawal is Altered after Prefrontocortical Dopamine Depletion in Rats: Monoaminergic Correlates

The objective of this study was to establish the effects of prefrontocortical dopamine depletion on opiate withdrawal and prefrontocortical neurochemical changes elicited by morphine dependence and withdrawal. The dopaminergic content was also measured in the nucleus accumbens during withdrawal, in order to detect reactive changes induced by prefrontocortical lesion. Withdrawal was induced by naloxone in morphine-dependent rats. Monoamine levels were analyzed post-mortem by high performance liquid cromatography. The results showed that chronic morphine dependence did not modify basal levels of monoamines in sham rats, revealing neuroadaptation of prefrontocortical dopamine, noradrenaline and serotonin systems to chronic morphine. The neuroadaptive phenomenon remained after prefrontocortical lesion (> 79% dopamine depletion). On the other hand, a strong increase of dopamine, noradrenaline, and serotonin contents in the medial prefrontal cortex of sham rats was detected during opiate withdrawal. However, in lesioned rats, the increase of prefrontocortical dopamine and serotonin content, but not that of noradrenaline, was much lower. In the nucleus accumbens, prefrontocortical lesion reactively enhanced the dopaminergic tone and, although opiate withdrawal reduced dopaminergic activity in both sham and lesioned rats, this reduction was less intense in the latter group. At a behavioral level, some symptoms of physical opiate withdrawal were exacerbated in lesioned rats (writhing, mastication, teeth-chattering, global score) and exploration was reduced. The findings hence indicate that: (i) prefrontocortical monoaminergic changes play a role in the behavioral expression of opiate withdrawal; (ii) the severity of some withdrawal signs are related to the dopaminergic and serotonergic tone of the medial prefrontal cortex rather than to the noradrenergic one, and (iii) an inverse relationship between mesocortical and mesolimbic dopaminergic systems exists.

Effect of homotaurine in experimental analgesia tests

1. The possible antinociceptive action of GABA A receptor agonist homotaurine, has been studied through a battery of chemical (acetic acid) and thermal (hot plate, tail flick and tail immersion) tests in rats and mice. 2. The aminoacid was used at the following doses 22.25; 55.62 and 111.24 mg/kg i.p. and 50-100 micrograms i.c.v.; and measurements were made at the time of and at 5, 15 and 30 min after drug administration. 3. Homotaurine exhibited a significantly antinociceptive effect in all the above mentioned test except hot plate and when administered i.c.v. in the tail flick test. 4. The antinociceptive effect in the chemical test was dose and time dependent. 5. In the tail immersion test, latency time for withdrawal of the tail was significantly increased with the dose of 55.62 mg/kg at 15 min and 111.24 mg/kg at 30 min. 6. In the tail flick test the antinociceptive effect was dose dependent at 15 and 30 min. 7. From the above results the implication of peripheral and spinal mechanisms in the antinociceptive effect of homotaurine may be concluded.

A possible interaction of potential clinical interest between digoxin and acarbose

This case report describes a 69‐year‐old woman with diabetes mellitus and heart failure who repeatedly had unusual subtherapeutic levels of plasma digoxin. When the drug therapeutic regimen was checked it was found that a new drug, acarbose, had been added to the therapeutic regimen before the unexpected laboratory reported results. Because other drugs included in her therapeutic menu were rejected as being responsible for decreased levels of digoxin, it was recommended to discontinue acarbose to evaluate its role. In the absence of acarbose, the plasma concentration of digoxin increased to the therapeutic range. We concluded that acarbose may be responsible for a pharmacokinetic interaction with digoxin by a still unknown mechanism. Although discontinuation of acarbose was recommended, the attending physician discontinued administration of digoxin because the clinical condition of the patient did not get worse during subtherapeutic levels of digoxin.

Role of GABAA and GABAB receptors and peripheral cholinergic mechanisms in the antinociceptive action of taurine

1. Gabaergic and cholinergic mediation in the antinociceptive effect of taurine has been investigated in mice (acetic acid test) and rats (tail-flick test). 2. Scopolamine sulfate and methylnitrate exhibit intrinsic antinociceptive activity and increase the effect of taurine in mice. 3. Baclofen also increases the antinociceptive effect of taurine in mice. 4. Anticholinergic agents and bicuculline but not CGP 35348 antagonize the effect of taurine in rats. 5. These results suggest that the antinociceptive effect of taurine may be partly mediated by spinal GABAA receptors and peripheral cholinergic mechanisms.

EFFECT OF PEPTIDYL‐DIPEPTIDASE INHIBITORS IN EXPERIMENTAL CONVULSIONS IN MICE

Summary— The anticonvulsant effect of compounds that inhibit peptidyl‐dipeptidase (PDP) on bicuculline (BIC)‐ and strychnine (STRYC)‐induced seizures was assessed after intracerebroventricular (ICV) or intraperitoneal (IP) administration in Swiss albino mice. STRYC‐induced seizures were delayed by ICV injections and high IP doses of captopril, but not by ICV or IP injections of enalapril or by lower doses of captopril (0.1 mg/kg and 1 mg/kg IP). BIC‐induced seizures were not suppressed by ICV or IP injections of either compound; on the contrary, captopril and enalapril exhibited proconvulsant effects when given IP or ICV by shortening the time of onset of tonic seizures and death. Results indicate that the anticonvulsant effect of captopril against STRYC‐induced seizures is not mediated by central γ‐aminobutyric acid (GABA) receptors or by the inhibition of PDP.

Age-related changes in the antinociception induced by taurine in mice

Taurine is a nonessential amino acid that is of medical interest for the nutrition of infants. Taurine has been found in the central nervous system of rodents and humans, and among its potential therapeutic uses, it is interesting to remark its analgesic actions. It is also well known that concentration levels during the fetal and prenatal periods are higher than in adulthood. The data obtained so far indicate that taurine is involved in the development process of the brain and possibly other organs. The taurine levels in old age are still unknown, but it is presumed that they will be different from those of younger animals. Data about age-related alterations and functional modifications of this and other amino acids are still scarce. The aim of the present work was to study the antinociceptive effect of taurine and its relationship with aging in mice. No differences were found between prepubertal and young adult animals; on the contrary, old animals showed significantly reduced sensitivity to the antinociception induced by taurine; in fact, at the tested doses, taurine did not induce antinociception in this group of mice. The mechanism underlying this effect has not been clarified because there are several mechanisms and neurotransmitter systems involved in the antinociception induced by taurine.

Role of K+‐channels in homotaurine‐induced analgesia

In previous articles, antinociceptive activity for homotaurine has been demonstrated to be mediated by opioid, GABAergic and cholinergic mechanisms. GABAB‐agonists affect K+‐channels and it is known that K+‐channels modulate specific activation of opioid receptors. In this study, we examined the involvement of K+‐channels in the antinociceptive activity of homotaurine (22–445 mg/kg). Antinociceptive response was obtained after icv pretreatment with the channel specific blockers 4‐aminopyridine (voltage‐dependent channels), tetraethylammonium (Ca++ and voltage‐dependent) and gliquidone (ATP‐dependent). The nociceptive tests performed were acetic acid induced abdominal constriction (mice) and tail flick (rats) tests. Acetic acid responses to homotaurine were inhibited by tetraethylammonium (5 μg) and gliquidone (16 μg). Tail flick response to homotaurine was inhibited by tetraethylammonium (50 μg), gliquidone (40 and 80 μg) and 4‐aminopyridine (25 and 250 ng). These results suggest an involvement of the three types of K+‐channels in antinociception by homotaurine, depending on specific homotaurine and blocker doses. At a spinal level, they appear to be involved together with GABAB and opioid mechanisms. Peripherally, only tetraethylammonium channels would be substantially activated during homotaurine antinociceptive effect.