M. R. Fennessy

Cardiovascular effects of intravenous morphine in the anaesthetized rat

Abstract The first intravenous injection of morphine in the anaesthetized rat produced a marked depressor response in doses from 0.01 to 100 mg/kg. This response appears to be mediated reflexly, the afferent pathways being in the vagus nerves and the resulting efferent effects consisting of a combination of vagal bradycardia and decreased sympathetic vasomotor tone. With high doses, direct cardiodepressant actions of morphine may contribute to the fall in blood pressure. Tachyphylaxis to the depressor effect developed slowly when repeated low doses were given, but very rapidly with high doses. The second injection of morphine in a dose of 10 mg/kg or more produced a pressor effect which was due mainly to increased sympathetic tone. There is also evidence of direct peripheral release of catecholamines.

Modification of morphine analgesia by drugs affecting adrenergic and tryptaminergic mechanisms

The effects of drugs that modify adrenergic or tryptaminergic mechanisms were tested on the analgesic action of morphine in mice. Analgesia was assessed by the hot plate method and phenylquinonewrithing method. Reserpine antagonized the analgesic action of morphine in both tests, the maximal effects occurring 6–8 h after the administration of reserpine. p‐Chlorophenylalanine antagonized the analgesic action of morphine as assessed by the writhing method but not by the hot plate method. The analgesic action of morphine was not modified in either test by pretreatment with α‐methyl‐p‐tyrosine, propranolol, phentolamine or methysergide. These results suggest that the analgesic action of morphine, as measured in the writhing test, may be mediated by 5‐hydroxytryptamine but that other mechanisms may be involved in the hot plate test.

THE EFFECT OF Δ9-TETRA-HYDROCANNABINOL ON BODY TEMPERATURE AND BRAIN AMINE CONCENTRATIONS IN THE RAT AT DIFFERENT AMBIENT TEMPERATURES

1 Rats were injected intravenously with 2 mg/kg (–)‐trans‐Δ9‐tetrahydrocannabinol (Δ9‐THC) at ambient temperatures of 4°, 21°, 31° and 37°C. 2 The general behaviour exhibited by rats treated with Δ9‐THC was similar at all four ambient temperatures. 3 Body temperatures were recorded continuously before and after drug administration. At 4° and 21°C, Δ9‐THC caused hypothermia whereas no change in body temperature occurred at 31° and 37°C. 4 The concentrations in the whole brain of noradrenaline (NA), dopamine, 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) were determined spectrophotofluorimetrically 1 h after drug administration. At 4°C Δ9‐THC caused an increase of 5‐HT, at 21°C an increase of 5‐HIAA, at 31°C an increase of 5‐HIAA and a decrease of NA, and at 37°C an increase of 5‐HT and 5‐HIAA. 5 At all ambient temperatures, Δ9‐THC increased the brain levels of 5‐HT and/or 5‐HIAA. A correlation between the Δ9‐THC‐induced hypothermic response and the possible alteration of brain 5‐HT metabolism cannot be excluded.

Biphasic nature of the effects of Δ9-tetrahydrocannabinol on body temperature and brain amines of the rat

The effects of i.v. injected delta9-tetrahydrocannabinol (delta9-THC) on behaviour, body temperature and levels of brain monoamines, measured spectrophotofluorimetrically, of the rat were determined. Doses of delta9-THC in the range of 0.05--5.0 mg/kg produced biphasic changes in behaviour, body temperature and levels of 5-hydroxyindoleacetic acid (5-HIAA). The whole brain levels of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) were not altered by delta9-THC. The subjective behavioural biphasic responses did not appear to be dose related, whereas the biphasic changes in body temperature and brain levels of 5-HIAA were dose-related. Low doses of delta9-THC (0.05 and 0.1 mg/kg) caused hyperthermia, while doses of 1.0, 2.0 and 5.0 mg/kg induced hypothermia. On the other hand, 0.05 mg/kg delta9-THC significantly reduced, whereas doses of 1.0, 2.0 and 5.0 mg/kg significantly increased the 5-HIAA levels in a dose-related manner. It is concluded that an inverse relationship exists between delta9-THC-induced changes in body temperature and alterations in brain 5-HIAA levels.

The relationship between morphine analgesia and the levels of biogenic amines in the mouse brain.

The effects of morphine on noradrenaline and 5-hydroxytyptamine levels in the mouse brain were determined fluorometrically. The doses of morphine used corresponded to its ED50 values in two analgesic tests. The ED50 of morphine in the phenylquinone-writhing test (0.85 mg/kg) produced a decrease only in 5-hydroxytryptamine levels of the brain whereas the ED50 for morphine in the hot plate test (8.5 mg/kg) reduced both noradrenaline and 5-hydroxytryptamine levels of the brain.

Effects of amantadine on uptake and release of dopamine by a particulate fraction of rat basal ganglia

Amantadine, in vitro, produced dose‐dependent blockade of dopamine uptake into a synaptosome‐rich particulate fraction of an homogenate of the basal ganglia of rats. A concentration of 3·6 times 10−6M was required to inhibit uptake by 50%. Diethazine was less potent in blocking dopamine uptake, the equiactive concentration being 8·0 times 10−6M. Amantadine and (+)‐amphetamine in concentrations in excess of 10−5M caused the release of small quantities of added dopamine from the particulate fraction.

Comparison of effect of morphine‐like analgesics on transmurally stimulated guinea‐pig ileum

1 . Morphine‐like analgesic drugs caused depression of twitches of the isolated guinea‐pig ileum in response to transmural electrical stimulation. The drugs tested were the narcotic analgesics codeine, diamorphine, fentanyl, morphine, morphine‐N‐oxide, normorphine, oxymorphone, pethidine, phenazocine and phenoperidine and the analgesic narcotic antagonists nalorphine and pentazocine. 2 . With the first application of one of these drugs the extent of depression of twitches was proportional to concentration. Except in the case of pethidine, there was no further depression when additional drug was added to the organ bath. With the second application of a drug after washing out the first dose, the depressant effect was less; that is, tolerance developed. With pethidine, the depression of twitches was proportional to concentration and tolerance could not be observed. 3 . When tolerance had been produced by cumulative addition of these drugs, a concentration was reached at which further addition resulted in increased activity of the ileum. 4 . With codeine, morphine and normorphine, the twitches were increased in height and regular. 5 . With diamorphine, fentanyl, oxymorphone, pentazocine, phenazocine and phenoperidine there were increased but irregular responses to transmural stimulation. 6 . Having reached the concentration at which these effects were observed, washout of the drug resulted in reduction of activity; the twitches became smaller or the irregular responses ceased. 7 . Readministration of a drug after activity of the ileum had been depressed by withdrawal of that drug resulted in restoration of activity, the ileum being dependent on the presence of the drug for its activity. 8 . Codeine and nalorphine did not produce as great an increase in activity on readministration to a dependent ileum as did morphine: they seem to act as partial agonists in producing this effect. 9 . In similar experiments with the isolated urinary bladder of the rat and guinea‐pig, morphine was less active in depressing responses to stimulation than it was on the ileum, and tolerance to the drug and dependence on it did not occur. 10 . These observations have been discussed in relation to analgesic activity, tolerance and dependence in man.

Comparison of the dose‐response effects of morphine on brain amines, analgesia and activity in mice

1 Noradrenaline, dopamine, 5‐hydroxytryptamine and 5‐hydroxyindoleacetic acid concentrations in the mouse brain were measured 30 min after subcutaneous injection of doses of morphine ranging from 01 to 100 mg/kg: motor activiy was also measured. 2 The noradrenaline concentration in the mouse brain was reduced by moderate (2 to 20 mg/kg) but not by high (above 20 mg/kg) and low (below 2 mg/kg) doses of morphine. 3 The dopamine concentration in the mouse brain was reduced by moderate (1 to 20 mg/kg) doses but was raised by high doses (above 20 mg/kg) of morphine. 4 The 5‐hydroxytryptamine concentration in the mouse brain was reduced by moderate (1 to 20 mg/kg) doses of morphine but not by high (above 20 mg/kg) and low (below 1 mg/kg) doses of morphine. 5 The 5‐hydroxyindoleacetic acid concentration was not affected by low doses (01 to 2 mg/kg), raised by a dose of 5 mg/kg, lowered by doses of 10–50 mg/kg and not affected by 100 mg/kg of morphine. 6 These results are discussed with reference to the possible implication of changes in monoamines for the analgesic and behavioural effects of morphine.

PHYSICAL DEPENDENCE IN THE RAT INDUCED BY SLOW RELEASE MORPHINE: DOSE‐RESPONSE, TIME COURSE AND BRAIN BIOGENIC AMINES

1. Physical dependence was induced in rats by administration of a slow release morphine emulsion (morphine SR), and assessed by scoring abstinence signs and temperature changes after i.p. administration of naloxone (5 mg/kg). Three groups of rats received doses of 75,100 or 150 mg/kg of morphine SR. Dependence was evaluated in each of these groups after 24, 48 and 72 h.

Involvement of capsaicin-sensitive afferent neurones in a vagal-dependent interaction between leukotriene D4 and histamine on bronchomotor tone

Leukotriene D4 (LTD4, 0.1–0.5 μg/kg, i.v.), administered 20 s before histamine (H, 1–4 μg/kg, i.v.), enhanced the bronchoconstrictor response to H by between 105 and 168%. Bilateral vagotomy, atropine or indomethacin each attenuated, whereas hexamethonium completely prevented, this enhancement. LTD4 failed to enhance the bronchoconstrictor effects of either acetylcholine (ACh) or electrical stimulation of the vagi. Capsaicin pretreatment reduced bronchoconstrictor responses to electrical stimulation of the vagi, but did not affect depressor responses. There was no interaction between LTD4 and H on bronchomotor tone in capsaicin-pretreated guinea-pigs. It is concluded that LTD4 enhances H-induced bronchoconstriction by a mechanism which involves an increased activity of efferent cholinergic nerves innervating the airways. However, the failure of LTD4 to enhance bronchoconstriction due to ACh or vagal stimulation, together with the prevention of the interaction between LTD4 and H by capsaicin-pretreatment, suggests that the site of the interaction may be on capsaicin-sensitive afferent neurones.