Antinociceptive Action Of Morphine Research Articles

Central depressant action of cesium in mice

Cesium chloride (CsCl) at several dose levels (1.25-20.0 mEq/kg IP) was administered acutely to albino mice whose behavior was compared with that in corresponding saline controls. Motor activity decreased and Straub tail occurred in a dose-related manner. Signs of autonomic disturbance, diarrhea, and salivation were seen with toxic doses. Subchronic administration of CsCl (5.0 mEq/kg/day IP for 7 days) exerted a phenothiazine-like effect in mice, reducing amphetamine-induced aggregation toxicity and enhancing pentobarbital-induced hypnosis. The antinociceptive action of morphine was unaltered by identical multiple administrations of CsCl. These results indicate a specific neurosuppressant action of CsCl on mouse CNS and suggest exploration of this alkali earth metal for antipsychotic-like activity.

Antinociceptive actions of morphine and buprenorphine given intrathecally in the conscious rat.

1 The antinociceptive effects of morphine and buprenorphine given intrathecally and subcutaneously have been compared in the conscious rat. 2 In the paw pressure test, when given subcutaneously buprenorphine 0.001-0.1 mg/kg s.c., was approximately 100 times more potent than morphine 0.1-3 mg/kg s.c., but in the hot plate test, buprenorphine 0.03-3.0 mg/kg s.c., produced a bell-shaped dose-response curve of low maximum effect and was about equipotent with morphine 0.03-3 mg/kg s.c. 3 When given intrathecally buprenorphine 10 micrograms and morphine, 10-60 micrograms, were approximately equipotent in both paw pressure and hot plate tests. Furthermore, morphine produced these effects at 1/25th of the minimum effective parenteral dose while the dose of buprenorphine exceeded the parenteral dose. 4 It is concluded that the predominant site of the analgesic action of buprenorphine is supraspinal. The significance of these findings in relation to the role of spinal opiate receptors is discussed.

Effects of morphine and indomethacin on single unit responses in the ventrobasal (VB) thalamus in adjuvant arthritic rats

Rats rendered polyarthritic by injection of Mycobacterium butyricum into the tail were used as a model of chronic pain. (1) The activities of 154 neurones in the VB thalamus have been recorded in adjuvant arthritic rats anaesthetized with urethane (1200mg/kg i.p.). The nature of neurones which had receptive fields located in inflamed areas of hind paw (115/154 in 48 rats) were studied. 16 neurones were activated only by non-noxious stimuli (nN neurone) such as brushing or tapping and displayed the classical properties of leminiscal responses. 92 neurones were activated only by noxious stimuli (N neurone) such as tibial joint movement induced by electrical stimulation (1 Hz, 5msec, 0.5-8mA and train 30) to inflamed areas of hind paw. A relatively large number of N neurones (28/92) displayed spontaneous paroxysmal discharge. 8 neurones responded to both noxious and non-noxious stimuli (NnN neurone). All these neurones displayed long lasting afterdischarge (2-12 times of duration of stimulation). 12 N neurones were stimulated with the intensity of 0.5 to 8mA. In 8/12 neurones, these discharge rates increased linearly with intensity, although the rates of the remaining 4/12 reached a plateau at an intensity of 4 to 6mA. (2) The anti-nociceptive action of morphine and indomethacin on evoked neuronal responses of the 62 VB thalamus N neurones were investigated. Morphine lmg/kg, i.v., indomethacin lmg/kg i.v. and indomethacin 3ug/rat i.vent., produced marked depressive actions on the VB neuronal responses to joint movement induced by electrical stimulation. Spontaneous activity was not significantly modified by these drugs.

Involvement of 5-hydroxytryptamine in the analgesic action of pethidine and morphine in mice.

1 Groups of mice were pretreated with the 5-hydroxytryptamine (5-HT) depletors, fenfluramine or p-chlorophenylalanine (PCPA), followed by pethidine or morphine. 2 Fenfluramine alone produced a short lasting analgesia but PCPA was without any effect. 3 Pethidine and morphine both increased hot plate reaction times measured after 30 min. 4 Pretreatment with PCPA attenuated morphine analgesia but did not affect pethidine analgesia. Fenfluramine did not alter the response to either analgesic. 5 PCPA produced a significant depletion of brain 5-HT levels which was not reversed by the analgesics. The fenfluramine-induced decrease in 5-HT was reversed by morphine but not by pethidine. 6 The results support the involvement of 5-HT in the antinociceptive action of morphine in the mouse.

Morphine- and methadone-tolerant mice differ in cross-tolerance to other opiates. Heterogeneity in opioid mechanisms indicated.

Mice were rendered tolerant to morphine or 1-methadone by subcutaneous injections for 4 days. The antinociceptive activities of morphine, codeine, l-methadone and d-propoxyphene were determined in tolerant and control mice using the hot-plate test, and the respective ED50's were calculated by the up-and-down procedure of Dixon. An asymmetry in cross-tolerance patterns was found: While morphine-pretreated mice were tolerant to morphine only (with a dose-ratio tolerant: control of 5.2), methadone-pretreated mice were tolerant to all analgesics tested, and more so to morphine 5.2; l-methadone 3.0; codeine 2.7 and d-propoxyphene 1.9). The results are discussed in terms of heterogeneity in opioid receptor mechanisms.

Evidence for the potentiation of the antinociceptive action of morphine by bromocriptine

The effect of bromocriptine on the antinociceptive activity of morphine has been studied in rats and mice. When administered alone, bromocriptine had no effect on the nociceptive state of the animal as reflected by the tail flick latency. However, in conjunction with morphine, bromocriptine significantly potentiated the anti-nociceptive action of morphine in both rats and mice. This potentiation was only observed at specific doses of bromocriptine and was susceptible to blockade by haloperidol. These results indicate that stimulation of at least some dopamine receptor types may modify the antinociceptive effect of morphine.

Is Fleming's lysozyme an analgesic agent? An experimental reappraisal of clinical data

Hen egg white lysozyme (Fleming's lysozyme) was tested for antinociceptive activity in rats against foot hyperalgesia provoked by a subplantar injection of a number of irritants: arachidonic acid, brewer's yeast, carrageenan, kaolin, mepartricin and rabbit anti-rat serum (Randall-Selitto method). The compound was active when given p.o., i.m.or i.v. (100-200-400 mg/kg) as well as when injected locally in the foot pad concurrently with the irritant (1-2-4 mg/rat). Lysozyme decreased the sensitivity of the imflamed paw to the nociceptive stimulation, left unmodified the sensitivity of the normal paw and did not reduce the oedema of the inflamed paw. It differed in its activity from steroidal and non-steroidal anti-inflammatory drugs and from central analgesics that were used as standard reference drugs. Its activity was not shared by hen egg white and ovalbumin. Contrary to dextran, lysozyme i.p. did not induce anaphylactoid reactions. Lysozyme did not provoke tolerance and did not interfere with the antinociceptive activity of morphine. The results are in agreementwith clinical data published years ago. Lysozyme was claimed to be an active analgesic agent against herpes zoster and cancer pain.

Effects of some GABA-mimetic drugs on the antinociceptive activity of morphine and beta-endorphin in rats.

Intracerebroventricular administration of muscimol, a potent GABA-receptor agonist, counteracted the antinociceptive effect of morphine or beta-endorphin in rats as measured by the "tail flick" method. Muscimol's activity was reversed by bicuculline. Isoguvacine, another GABA agonist, as well as nipecotic acid and guvacine, two inhibitors of neuronal and glial uptake of GABA, also antagonized morphine's antinociceptive effect. A role of the central GABA-ergic system in mediating opiate antinociception is proposed.

Antinociceptive action of morphine on unit activity in the nucleus of amygdala in the cats

Antinociceptive action of morphine on unit activity in the nucleus of amygdala in the cats

Opiate receptor antagonism by l-prolyl-l-leucyl-glycinamide, MIF-I

Chronic administration of l-prolyl-l-leucyl-glycinamide (MIF-I) to mice slightly reduced morphine's antinociceptive activity in the hot-plate test and modified the biphasic motor activity response to morphine. MIF-I antagonized the initial depression of activity and potentiated the increased motor activity phase. Chronic treatment of rats with MIF-I prevented morphine's antinociceptive activity in the tail flick test. MIF-I partly antagonized the inhibition by morphine of the coaxially stimulated guinea-pig ileum preparation. The inhibition of the ileum produced by ethylketocyclazocine was weakly antagonized by MIF-I. In contrast, MIF-I had no effect on the inhibition of the stimulated mouse vas deferens produced by Leu-enkephalin. The findings show that MIF-I weakly and selectively inhibits μ-type opiate receptors which suggests that MIF-I could be an endogenous inhibitor of opiate receptors.

The effect of aspirin and paracetamol on the increased naloxone potency induced by morphine pretreatment

Using the abdominal constriction test in mice, it was shown that pretreatment with a single dose of morphine given 3 h previously caused a marked increase in the antagonistic effect of naloxone without any change in the antinociceptive action of morphine itself. Pretreatment with either paracetamol (10.0–20.0 mg/kg, s.c.) or aspirin (5.0–10.0 mg/kg, s.c.) caused a small but significant antagonism of the antinociceptive effect of morphine, while the antagonistic action of naloxone remained unaffected. However, when aspirin or paracetamol was administered with morphine in the pretreatment regime, the ability of morphine to induce an increase in naloxone potency was much attenuated. This inhibitory effect was dependent on the dose of aspirin or paracetamol used in the pretreatment regime. The antinociceptive effect of aspirin and paracetamol was also studied. In the doses used, they did have a mild antinociceptive effect, but the analgesic effect of morphine was not affected by the administration of these drugs 30 min beforehand. It is suggested that the antinociceptive effect of morphine is probably not dependent on prostaglandin, but that the induction of increased naloxone potency is likely to be mediated through prostaglandin synthesis.

Further studies on opiate receptors that mediate antinoception: tooth pulp stimulation in the dog.

1 The antinociceptive activities of morphine, codeine and dextropropoxyphene (micro-agonists), buprenorphine and Mr 2034 [(-)5,9-dimethyl-2-(tetrahydrofurfuryl)-2'-hydroxy-6,7-benzomorphan](k-agonists ) have been determined against nociceptive responses to electrical stimulation of the tooth pulp in the conscious dog. 2 Dose-dependent increases in nociceptive threshold were obtained for all of the analgesic drugs tested at doses within their antinociceptive range as determined in nociceptive pressure and chemical tests in rodents.

The influence of 5-HT receptor blocking agents on the behavioral effects of analgesics in rats.

The influence of methergoline, methysergide, mianserine, cyproheptadine, and pizotifen on catalepsy induced by morphine, codeine, and fentanyl, and antinociception induced by these three drugs and by pentazocine was studied in rats. Methergoline dose-dependently reduced catalepsy induced by these three drugs. Methysergide abolished only morphine catalepsy, while mianserine significantly reduced the effect of morphine and codeine. Cyprohepatide and pizotifen did not modify the cataleptic effect of the three analgesics used. Antinociceptive action of morphine, codeine, fentanyl, and pentazocine, measured by the hot plate method, was not influenced or changed differentially by any serotonin receptor blocking compounds. One may conclude that catalepsy induced by morphine is, in general, antagonized by serotonin receptor blockade, but this does not concern all narcotic analgesics. In the antinociceptive effects of drugs used, the serotonergic influence seems to play a less important role than in catalepsy.

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 effect of pentobarbital on the antinociceptive action of morphine in morphine-tolerant and non-tolerant rats

The interaction of sodium pentobarbital with morphine sulfate in both morphine-tolerant and non-tolerant rats was investigated using the tail-compression test for analgesia. Male Sprague-Dawley rats (300–350 g) were given pentobarbital (4, 8, or 16 mg/kg) 5 min before morphine (2, 4, 6, or 8 mg/kg). Control animals received two saline injections, or pentobarbital plus saline, or saline plus morphine. All injections were subcutaneous. Prior to the first injection, a baseline nociceptive threshold was determined for each rat by applying a modified micrometer to its tail and increasing the pressure until a squeak was elicited. Test readings were taken every half-hour for 2 hr beginning 30 min after the second injection. For the chronic studies, animals were first made tolerant to morphine by the administration of the narcotic twice a day for 3 days, increasing the dose from 10 to 50 mg/kg/injection. Identical testing procedures were then followed with these rats except that the test dose of morphine given on day 4 was in the range 8–128 mg/kg. It was found that Na pentobarbital, in the subanesthetic doses used, had neither antinociceptive nor hyperalgesic properties. Furthermore, the barbiturate had no effect on the antinociceptive action of morphine in either morphine-tolerant or non-tolerant rats.

Further studies on the role of cholinergic mechanisms in the development of increased naloxone potency in mice

Using the abdominal constriction response in mice, it was shown that pretreatment with either pilocarpine (5.0 mg/kg, s.c.) or oxotremorine (0.05–0.10 mg/kg s.c.) caused a small but significant potentiation of the antinociceptive effect of morphine and the antagonistic action of naloxone. The potentiation of naloxone was considerably augmented following pretreatment with morphine plus either pilocarpine (2.5–5.0 mg/kg) or oxotremorine (0.05–0.10 mg/kg) as compared with any of these drugs given alone. Pretreatment with atropine sulphate (2.0 mg/kg, s.c.) had no effect on naloxone potency nor on the antinociceptive activity of morphine, but somewhat reduced that of pilocarpine and oxotremorine. Atropine abolished the ability of morphine pretreatment to enhance naloxone potency, and greatly reduced the augmenting effect of morphine plus the muscarinic receptor agonist drugs. It was also shown that oxotremorine reduced the development of dependence on morphine as tested by naloxone-precipitated jumping. These results agreed well with those reported using anticholinesterase drugs and add further evidence that the cholinergic system does play a role in the development of increased naloxone potency caused by morphine pretreatment. The increased naloxone potency does not seem to be related to the development of “acute dependence” on morphine.

Development of morphine tolerance and physical dependence in rats depleted of brain catecholamines by 6-hydroxydopamine

The present study was undertaken to evaluate the roles of brain norepinephrine (NE) and/or dopamine (DA) in the development of morphine tolerance and physical dependence in rats. Rats were permanently depleted of brain catecholamines (CA, i.e. NE + DA) or DA by 6-hydroxydopamine (6-OHDA) treatment alone or desmethylimipramine plus 6-OHDA treatment at two weeks of age. Five weeks after either treatment, twice daily morphine injections were begun and continued for 32 consecutive days. The antinociceptive activity of morphine in the tail-flick test and the naloxone-precipitated abstinence syndrome were periodically observed throughout the course of chronic morphine treatment. A decreased antinociceptive response to morphine occurred in DA-depleted rats in both the non-tolerant and tolerant states, but the development of tolerance was not affected. The antinociceptive effect of morphine was not modified in either non-tolerant or tolerant CA (NE + DA)-depleted rats, nor was the development of tolerance affected. The spontaneous withdrawal syndrome after abrupt cessation of morphine after 32 days of treatment was markedly enhanced in CA-depleted rats. The results suggest that DA may be involved in mediating the antinociceptive effect of morphine, but not in the development of tolerance to that effect.

The antinociceptive effect of intracerebroventricularly administered prostaglandin E1 in the rat.

It is generally accepted that prostaglandins (PGs) are nociceptive substances. However, earlier studies from this laboratory indicated that morphine analgesia, in the rat, was not only serotonin mediated, but involved PGs as well. Several PG synthesis inhibitors were shown to inhibit morphine analgesia and PGE1 was shown to potentiate the antinociceptive effect of morphine. Intraperitoneal administration of PGE1, but not PGE2 and PGF2alpha, elicited antinociceptive effect per se, by the radiant heat method. The present study was undertaken to confirm the antinociceptive action of PGE1, after intracerebroventricular administration, against nociceptive impulses induced by radiant heat, pressure, and high frequency electric current. PGE1 produced a dose-dependent antinociceptive effect by the radiant heat and pressure methods. It potentiated the antinociceptive action of morphine by the electrical stimulation method. The antinociceptive action of PGE1 was not evident in 5,6-dihydroxytryptamine-pretreated rats, suggesting that this effect is serotonin mediated. The present study thus confirms the antinociceptive action of PGE1 and suggests that, unlike its peripheral action, the central action of PGE1 results in suppression of nociceptive responses which may be serotonin mediated.

The effects of a permanent and selective depletion of brain catecholamines on the antinociceptive action of morphine.

6-Hydroxydopamine was given to newborn mice. After 60 days their brains were deficient in noradrenaline and dopamine while morphine's antinociceptive action was reduced. 6-Hydroxydopa was administered to adult mice. This depleted brain noradrenaline and reduced morphine's antinociceptive action. Newborn rats received 6-hydroxydopa. After 60 days morphine's antinociceptive action was potentiated, brain noradrenaline was reduced while dopamine had increased. Adult rats were treated with 6-hydroxydopa. This reduced brain noradrenaline but did not affect morphine's antinociceptive action. Guanethidine, which depletes noradrenaline in the peripheral nervous sytem, was given to newborn animals of both species. It had no effect on morphine's antinociceptive action. It is concluded that in the mouse the antinociceptive action of morphine relies in part on normal brain noradrenaline function and dopamine is not directly involved. In the rat morphine's action is affected by neurotoxic drugs which alter brain dopamine function.

Effect of some prostaglandin synthesis inhibitors on the antinociceptive action of morphine in albino rats.

1. Five prostaglandin synthesis inhibitors, indomethacin, diclofenac, mefenamic acid, ibufen and paracetamol, were found to inhibit the antinociceptive action of morphine without affecting the antinociceptive response of an equi-analgesic dose of prostaglandin E1. 2. Diclofenac was found to be the most potent and longest acting, whereas paracetamol was the least potent and shortest acting. Indomethacin, mefenamic acid and ibufen occupied an intermediate position, both in potency and duration of action. 3. The results suggest that prostaglandins may be involved in the antinociceptive action of morphine in albino rats.