Potentiation Of Morphine Analgesia Research Articles

Increased sensitivity of the central nervous system to morphine analgesia by amitriptyline in naive and morphine-tolerant rats

The effects of amitriptyline (AT) (20 mg/kg, i.p.), given 1 hr before [ 14C]morphine administration, on the analgesic response and tissue distribution of [ 14C]morphine and [ 14C]morphine glucuronide (MG) were studied in naive and morphine-tolerant rats. Rats were rendered tolerant to morphine analgesia by s.c. implantation for 3 days of a pellet containing 75 mg of morphine base. In naive rats, AT treatment increased the intensity and prolonged the duration of morphine analgesia. Amitriptyline treatment did not cause any significant change in the concentrations of [ 14C]morphine in the brain or of total 14C in the plasma 30, 60 and 90 min after administration of [ 14C]rnorphine. With the exception of a slight increase in total 14C in the liver at 30-min, AT treatment did not affect the concentrations of total 14C in the liver and urine. The fact that the percentages of total 14C in the liver or urine as [ 14C]MG were not changed by AT treatment suggests that AT did not affect biotransformation of morphine. This suggestion was supported by our previous report that a metabolic drug interaction with morphine would be reflected by a change in the percentage of total 14C as [ 14C]MG in the liver and urine [S.J. Liu and R.I.H. Wang, Drug Metab. Dispos. 8, 260 (1980)]. Potentiation of morphine analgesia, similar to that seen in naive rats, was also found in morphine-tolerant rats. The brain concentration of [ 14C]morphine in AT-treated morphine-tolerant rats at 60-min was lower than that in controlled morphine'-tolerant rats. However, the concentrations of total 14C in liver and urine and the percentage of total 14C in liver or urine as [ 14C]MG were not changed significantly by AT treatment in morphine-tolerant rats. It was concluded that AT treatment prolonged morphine analgesia by increasing the sensitivity of the central nervous system to morphine rather than by changing morphine pharmacokinetics.

Effects of amino acids, especially taurine and γ-aminobutyric acid (GABA), on analgesia and calcium depletion induced by morphine in mice

The analgesic effect of morphine was antagonized in mice by intracerebroventricular pretreatment with taurine, γ-aminobutyric acid (GABA) or glycine and was potentiated by ethylene glycol tetra-acetic acid (EGTA) but not altered by L-glutamate or L-aspartate. The potentiation of morphine analgesia by EGTA was reversed by a concentration of taurine that did not alter the tail-flick response. The selective depletion of 45Ca 2+ from synaptic vesicles observed with morphine administration was significantly inhibited by taurine injection (1.2 μmol/brain, i.vt.) but was not altered by the same dose of GABA. Inhibition of ATP-dependent 45Ca 2+ uptake in synaptosomes by morphine was also completely reversed by taurine (10 −2 M) which by itself did not alter 45Ca 2+ uptake. These results suggest that antagonism of morphine analgesia by taurine may be caused by blockade of the morphine-induced inhibition of both ATP-dependent synaptosomal 45Ca 2+ uptake and changes in synaptic vesicular 45Ca 2+ localization, while the antagonism by GABA was not associated with synaptosomal Ca 2+.

Opioid and non-opioid stress analgesia: assessment of tolerance and cross-tolerance with morphine

Opioid and non-opioid mechanisms of analgesia elicited by two kinds of footshock stress that differ only in temporal characteristics previously have been inferred on the basis of susceptibility to naloxone blockade. The present study sought further evidence on this point by comparing these two kinds of footshock analgesia for possible tolerance development and cross-tolerance with morphine. It was found that, with repeated exposure to stress, tolerance developed to naloxone-sensitive, but not naloxone-insensitive, stress analgesia. Furthermore, morphine-tolerant rats displayed cross-tolerance to only the naloxone-sensitive form of footshock analgesia. Although prior exposure to both footshock paradigms potentiated morphine analgesia, less potentiation occurred in rats tolerant to the naloxone-sensitive footshock stress. Thus, cross-tolerance between morphine and this type of stress analgesia appears to occur in both directions. These findings are consistent with those using naloxone antagonism as a criterion for opioid mediation and support the conclusion that separate opioid and non-opioid mechanisms of stress analgesia exist.

Antinociceptive activity of clonidine and its potentiation of morphine analgesia

Pain: February 1981 - Volume 10 - Issue 1 - p 119 doi: 10.1016/0304-3959(81)90067-1

Opiate and peptide interaction: Effect of enkephalins on morphine analgesia

Interactions between the weakly analgesic enkephalins and morphine on morphine-induced analgesia were studied. Met-enkephalin exhibited morphine analgesia whereas Leu-enkephalin potentiated it. Both Met- and Leu-enkephalin, when tested alone, were not analgesic. The strongly analgesic FK33824 (Sandoz) compound, like Leu-enkephalin, also potentiated morphine analgesia. Tolerance developed to morphine analgesia but not to Met-enkephalin inhibition of morphine analgesia.

Effects of glycine, beta-alanine and diazepam upon morphine-tolerant-dependent mice.

The effects in mice of glycine, beta-alanine and diazepam on the analgesic response to morphine, on the intensity of tolerance and on the physical dependence on the analgesic have been examined. The two amino acids increased the analgesic response to morphine in a dose-related manner. However, both compounds were ineffective in the analgesic test (hot plate) when administered without morphine. Diazepam was ineffective in the analgesic test and it did not alter morphine analgesia, except when administered in a high dose which decreased and analgesic response. Glycine, either in single or repeated doses, did not modify tolerance to morphine, whereas beta-alanine induced a dose-related partial antagonism, which promptly reached a plateau. Diazepam induced a small decrease in the intensity of tolerance to the analgesic. The abstinence syndrome to morphine, induced by naloxone administration to primed mice, was reduced by single doses of glycine or beta-alanine. Diazepam behaved as a weak inhibitor of the abstinence syndrome when administered at a high dose. The potentiation of morphine analgesia and the antagonism of the abstinence syndrome induced by the amino acids may be related to their hyperpolarizing action in the c.n. system. The effects of beta-alanine on morphine tolerance cannot be explained by the same mechanism.

Antinociceptive activity of clonidine and its potentiation of morphine analgesia

The activity of clonidine and its interaction with morphine was assesed in the mouse tail flick assay. In this assay, clonidine was found to be 10 times more potent than morphine. Clonidine potentiated morphine antinociceptive activity approximately five-fold and morphine potentiated clonidine activity four-fold. Clonidine's agonistic activity was not reversed by naloxone hydrochloride 910 mg/kg) while the potentiating effect of clonindine by morphine was. Tolerance to the antinociceptive effect of morphine was observed in morphine pellet-implanted mice byt no cross tolerance was observed for clonidine. These data indicate that clonidine-induced analgesia is not a result of an interaction at morphine receptors; but rather, common pathway(s) are present which appear to complement the agonistic interaction of each.

The effects of divalent ions on morphine analgesia and abstinence syndrome in morphine-tolerant and-dependent mice

Intracerebral administration of copper sulfate potentiated morphine analgesia in morphine-tolerant and -dependent mice, but copper failed to affect other abstinence signs. When abstinence was precipitated with a partial antagonist, nalorphine, stereotyped jumping was not inhibited by either calcium or copper. These modifications of narcotic effects by copper were produced without alterations in the brain disposition of morphine. Total radioactivity in the brain following radioactive naloxone administration was also not altered.

Potentiation of morphine analgesia in mice after inhibition of brain type b monoamine oxidase

Morphine analgesia in mice was significantly potentiated by deprenyl and pargyline, selective inhibitors of brain type B monoamine oxidase (MAO). Clorgyline and Lilly 51641, selective inhibitors of type A MAO, did not modify the morphine effect. Morphine analgesia was also potentiated by increasing the dose of Lilly 51641 so as to block type B MAO by about 70%, or by inhibiting unspecifically both enzyme forms after either tranylcypromine or high doses of pargyline. No general correlation was found between an increased brain concentration of morphine and the enhancement of morphine analgesia induced by some of the MAO inhibitors tested. 2-Phenylethylamine, a specific substrate of type B MAO, was also found to potentiate morphine analgesia. It is suggested that endogenous substrates of type B MAO may modulate the opiate receptor binding.

Potentiation of morphine analgesia by muscimol

The injection of 0.15 to 0.2 mg/kg of muscimol intravenously, lowered the ED 50 dose of morphine in mice and rats. Maximal tolerated doses of muscimol failed to cause alangesia when injected alone

Morphine tolerance and physical dependence: Influence of cholinergic agonists and antagonists

The effects of centrally acting agents which alter cholinergic activity were assessed in mice rendered tolerant to and dependent on morphine (M mice) and in naive mice (N mice). In both N and M mice, physostigmine potentiated morphine analgesia slightly, and this action was blocked by atropine and scopolamine. When administered 10 min before naloxone in dependent mice atropine enhanced precipitated withdrawal jumping; when given 30 min before naloxone, atropine produced an inhibition of the response. Physostigmine and oxotremorine greatly inhibited the jumping response, while echothiophate had no effect. The inhibitory effect of physostigmine on naloxone precipitated withdrawal jumping was reversed by atropine and scopolamine but atropine did not alter morphine tolerance and dependence development. Brain acetylcholine (ACh) levels in both N and M mice were increased by physostigmine, the increase being greater in M mice. This increase was blocked by prior administration of atropine or scopolamine. When atropine was administered to M mice 10 min before sacrifice, brain ACh levels decreased. However, when brain ACh levels were determined 30 min after atropine, no change was found. It was concluded that ACh does not play a major, direct role in the development of tolerance and dependence, but that ACh is involved in the manifestations of acute morphine effects and in some of the withdrawal signs in the dependent state.

SOME INTERACTIONS BETWEEN MORPHINE AND DIAZEPAM IN THE MOUSE AND RABBIT

Some interactions between diazepam and morphine have been examined in the conscious animal, looking particularly at respiratory effects in the rabbit and the relationship between respiratory depression and analgesia in the mouse. Some evidence of potentiation of the respiratory effects of morphine was found in both species. This was manifest as Pco2, changes in the rabbit and depression of respiratory rate in the mouse. No separation between potentiation of morphine analgesia and respiratory rate depression, by diazepam, was found in the mouse.

Plasma copper levels and their significance in morphine analgesia and tolerance

Morphine lowered plasma copper content. However after of sodium diethyldithiocarbamate, which decreased the copper level markedly and potentiated morphine analgesia, it caused no further decrease. This action of morphine was antagonized by levallorphan which elevated plasma copper concentration. In morphine tolerant rats, there was a marked increase in plasma copper level which was partially reversed by morphine withdrawal. When sodium diethldithiocarbamate was administered to the morphine tolerant animals, morphine analgesia reappeared, and the elevated copper level was markedly decreased. These results indicate that the changes in copper level in plasma, or the mechanisms mediating these alterations and/or the results caused by these fluctuations may be related to the manifestation of morphine analgesia and tolerance.

Potentiation of morphine analgesia by cocaine in mice

The interaction between morphine and cocaine in producing analgesia in mice has been studied. To investigate the mechanism of this interaction, some other local anaesthetics and amphetamine and imipramine were tested in combination with morphine. The effect of pretreatment with reserpine, or of treatment with the antiadrenaline drug phentolamine, was examined. The potency of each local anaesthetic in potentiating noradrenaline was assessed. Cocaine potentiated morphine analgesia. Procaine and lignocaine, though less potent, were also effective, but cinchocaine was not. Hence, ability to potentiate morphine was not related to local anaesthetic activity. Involvement of the sympathomimetic action of cocaine was indicated because (1) the potencies of cocaine, procaine and lignocaine in potentiating morphine were related to their potencies in potentiating noradrenaline, (2) reserpine antagonized the actions of morphine and morphine-cocaine combinations and (3) amphetamine potentiated morphine. However imipramine did not increase and phentolamine did not reduce the action of morphine.

Analgesic Action of Chlorpromazine and Reserpine in Relation to that of Morphine

Abstract An analgesic action of reserpine is reported in mice. This effect, detected by the hot-plate method, is of little, or only of moderate intensity, in the first 2 hr. after injection; maximal intensity is obtained 48–72 hr. after the injection of the drug, and then decreases gradually; after 144 hr. injected animals behave again like controls. The analgesic effect of reserpine seems to differ from that shown by morphine or that shown by chlorpromazine which is quicker in onset and disappears in a few hours. Reserpine potentiates the analgesic action of morphine. This potentiation can be observed 2 hr. after the injection of reserpine. The early potentiating period is followed by a later period of summation of effects. Since a short interval after the injection, reserpine does not exert any analgesic effect, but is able to potentiate morphine analgesia, this action has been regarded as a direct one; the later period of analgesia and summation of effects with morphine has been interpreted as an indirect action of the drug

The Use of Noscapine (Narcotine) as an Antitussive Agent

and similar compounds is based on a phenanthrene nucleus, whereas Noscapine is an isoquinoline derivative (related to papaverine). It is readily absorbed after oral or parenteral administration, disappears rapidly from the blood stream, and only traces appear in the urine. Its fate is unknown. It has been referred to as the least toxic of the opium alkaloids in mice, rats, and man. Up to 3 grams by mouth have been given to man with only minor side reactions. Chronic toxicity studies did not demonstrate any cumulative effects. No depressant action on respiration or the central nervous system has been observed up to toxic doses; stimulation may appear with higher doses. The effects of Noscapine on the gastrointestinal tract were insignificant. No effects on secretory activity and minimal effects on gastrointestinal movements were reported. Occasionally emesis and constipation were noted only with large doses. No significant analgesc action was observed. Potentiation of morphine analgesia with antagonism to side effects have been reported, but not definitely established. The parenteral use of Noscapine has been limited because of local pain. In experimental cough in animals and man, it was described as effective as codeine. No tolerance to the drug developed. Finally, although no antihistaminic action was found, it did inhibit the “allergic cough” in sensitized guinea pigs exposed to aerosols of specific antigen. It did not, however, prevent anaphylactic shock after injected antigen. In a study centering about the experimental production of cough in normal and asthmatic subjects, small doses of Narcotine (5 and 15 mg.) were demonstrated to have greater anti