Paolo Mantegazza

Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study.

Although it is well known that morphine induces significant immunosuppression, the potential immunosuppressive activity of morphine derived drugs commonly used in the treatment of pain (codeine, hydromorphone, oxycodone) has never been evaluated. We evaluated in the mouse the effect of the natural opiates (morphine and codeine) and synthetic derivatives (hydromorphone, oxycodone, nalorphine, naloxone and naltrexone) on antinociceptive thresholds and immune parameters (splenocyte proliferation, Natural Killer (NK) cell activity and interleukin‐2 (IL‐2) production). Morphine displayed a potent immunosuppressive effect that was not dose‐related to the antinociceptive effect, codeine possessed a weak antinociceptive effect and limited immunosuppressive activity; nalorphine, a μ‐antagonist and κ‐agonist, exerted a potent immunosuppressive effect, but had very weak antinociceptive activity. The pure κ‐antagonist nor‐BNI antagonized the antinociceptive, but not the immunosuppresive effect of nalorphine. Hydromorphone and oxycodone, potent antinociceptive drugs, were devoid of immunosuppressive effects. The pure antagonists naloxone and naltrexone potentiated immune responses. Our data indicate that the C6 carbonyl substitution, together with the presence of a C7‐8 single bond potentiates the antinociceptive effect, but abolishes immunosuppression (hydromorphone and oxycodone). The single substitution of an allyl on the piperidinic ring resulted in a molecule that antagonized the antinociceptive effect but maintained the immunosuppressive effect. Molecules that carry modifications of C6, the C7‐8 bond and C14, together with an allyl or caboxymethyl group on the piperidinic ring antagonized both the antinociceptive and the immunosuppressive effect of opiates and were themselves immunostimulants.

A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs

The analgesic effect of acute or chronic nortriptyline, amitriptyline and their effects on morphine induced analgesia were evaluated in the rat. Clomipramine and amitriptyline, but not Nortriptyline, induce analgesia, while all potentiate the effect of morphine when administered acutely. The analgesic effect of clomipramine is blunted by both the serotonin antagonist metergoline and the opiate receptor blocker naloxone, thus indicating an involvement of both the serotoninergic and endogenous opioid system. The involvement of the serotoninergic system is confirmed by the similar results obtained with the serotonin precursor 5-hydroxytryptophan administered alone or together with morphine. A relation between the serotoninergic and the endogenous opioid systems is also shown by the increase in hypothalamic beta-endorphin concentrations elicited by all the drugs used after acute or chronic treatment, with the only exception of nortriptyline, that has been shown to exert its effects mainly through the noradrenergic system. In conclusion, the analgesic effect of clomipramine and amitriptyline and their potentiation of morphine induced analgesia seems to be related to an activation of the endogenous opioid system mediated by serotonin.

Decreased antinociceptive activity of morphine in rats pretreated intraventricularly with 5,6-dihydroxytryptamine, a long-lasting selective depletor of brain serotonin.

The antinociceptive activity of morphine was measured in rats treated with 5,6-dihydroxytryptamine, through cannulae chronically implanted into both lateral ventricles of the brain.This indoleamine, which induces a selective degeneration of serotoninergic nerve terminals in the central nervous system, markedly decreased the effect of morphine. The possible role of 5-hydroxytryptamine on antinociceptive activity of morphine is discussed.

MODIFICATION OF THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY CENTRALLY ADMINISTERED DIAZEPAM AND MIDAZOLAM

1 Intracerebroventricular administration of diazepam or midazolam decreased the antinociceptive effect of morphine in rats as measured by the ‘tail flick’ method. 2 Midazolam, injected into the periaqueductal grey matter (PAG) antagonized the analgesic effect of morphine. The action of midazolam was partially reversed by bicuculline. 3 These findings support the view that the effect of benzodiazepines on morphine antinociception may be mediated through γ‐aminobutyric acid receptors.

Central effects of tumor necrosis factor α and interleukin-1α on nociceptive thresholds and spontaneous locomotor activity

Abstract To extend the knowledge on the central effects of cytokines, we studied the effects of tumor necrosis factor α and interleukin-1α on nociceptive thresholds and spontaneous locomotor activity in rats. After central administration, both tumor necrosis factor α and interleukin-1α significantly ( P

AMPHETAMINE-LIKE ACTIVITY OF β-PHENETHYLAMINE AFTER A MONOAMINE OXIDASE INHIBITOR IN VIVO

β‐Phenethylamine possesses marked amphetamine‐like effects which are demonstrable in animals pre‐treated with a monoamine oxidase inhibitor. Like amphetamine, β‐phenethylamine induces an increase of coordinated spontaneous motility in mice, anorexia in rats and dogs, hyperthermia in mice and rats, and exhibits a difference in lethality between isolated and aggregated mice. These effects are seen with similar doses of β‐phenethylamine or amphetamine. But, unlike amphetamine, β‐phenethylamine does not increase coordinated spontaneous motility in rats.

Reduction of food intake by apomorphine: A pimozide-sensitive effect

brain 5-HT and 5-HIAA and preventing 5-HT accumulation after pargyline. Thus D-PCPA, like its L-isomer, inhibits 5-HT synthesis. As previously shown for the racemic compound (Koe & Weissman, 1966), the depletion of brain 5-HT and 5-HIAA induced by Dor L-PCPA was maximal after a long latency and persisted for several days. These results suggest that the inhibition of 5-HT synthesis by either isomer is an irreversible process and depends on the slow formation of an active metabolite. Since D-amino acids are not incorporated into proteins (Berg, 1959), the incorporation of D-PCPA into tryptophan hydroxylase is unlikely. A conversion of D-PCPA in vivo to L-PCPA is theoretically possible via its deamination by D-amino acid oxidase (Blaschko & Stiven, 1950) to p-chlorophenylpyruvic acid followed by transamination of the latter to L-PCPA (Spencer & Brock, 1962). However, this is difficult to reconcile with the fact D-PCPA decreases the level of 5-HT and 5-HIAA at the same rate, to the same extent, and for the same time as the L-isomer. These considerations lead to the conclusion that stereoisomerism is not essential for PCPA-induced inhibition of 5-HT synthesis.

Dissociation of tolerance and dependence to morphine: a possible role for cholecystokinin.

Since cholecystokinin (CCK) has been suggested to be an endogenous opiate antagonist, we tried to evaluate if this peptide could be involved in the development of tolerance to morphine. Naive rats were chronically administered morphine, either alone or concomitantly with proglumide or benzotript, two putative CCK receptor antagonists. Chronic treatments with both CCK antagonists alone were also established. Drugs were administered by the oral route, dissolved in the drinking water. At the end of the chronic treatments, the development of tolerance to morphine was assessed by an evaluation of the analgesic responses evoked by graded doses of acutely injected morphine in the tail-flick and hot plate tests. Proglumide and benzotript were able to inhibit the shift to the right of the dose-response curve for morphine, i.e. they prevented the development of tolerance to morphine-induced analgesia. Chronically given alone, the two CCK antagonists never modified the responses to the acute challenge with morphine. We also determined the development of physical dependence by looking at the withdrawal syndrome precipitated by graded doses of acutely injected naloxone. In these experiments the concomitant treatment with morphine and proglumide or benzotript did not modify the occurrence of dependence. These observations are consistent with the hypothesis of CCK being an endogenous opiate antagonist, involved in the development of tolerance to morphine-induced analgesia but not of dependence. Moreover, tolerance to and dependence on morphine can be pharmacologically dissociated.

Effect of aspirin on serotonin and met-enkephalin in brain: correlation with the antinociceptive activity of the drug

Intravenous administration of acetyl salicylate of lysine, a soluble salt of aspirin, reduced in rats the firing discharge of thalamic neurones, evoked by noxious stimuli. Concomitantly, concentrations of 5-hydroxyindole acetic acid increased, while those of met-enkephalin-like immuno-reactive derivatives were decreased in several areas of the brain. Similar electrophysiological and biochemical responses were obtained by administering tryptophan or 5-hydroxytryptophan plus carbidopa. The effect of aspirin on the evoked firing of the thalamic neurones was counteracted by pretreating the animals with metergoline. On the other hand, naloxone did not antagonize the inhibitory effect of aspirin and 5-hydroxytryptophan on pain-induced neuronal excitation. These data indicate that a serotonin-, but not a naloxone-sensitive opiate mechanism, may be relevant for aspirin-mediated antinociception.

Periaqueductal gray matter involvement in the muscimol-induced decrease of morphine antinociception

SummaryMicroinjections of muscimol, a GABA receptor agonist, into the periaqueductal gray matter (PAG) counteracted the antinociceptive effect of morphine in rats, as measured by the “tail-flick” method. Muscimols effect was partially reversed by bicuculline.