Interaction of adenosine analogs with morphine in analgesic tests.

The effect of selective adenosine receptor agonists on nociceptive responses of mice and rats and on morphine analgesia was investigated. All compounds used: phenylisopropyladenosine (R-PIA), adenosine ethylcarboxamide (NECA), cyclohexyladenosine (CHA) and 2-chloroadenosine (2-CADO) exhibited antinociceptive action in mice and rats in the hot-plate (56 degrees C) and tail-immersion (52 degrees C) tests. R-PIA, CHA and NECA potentiated the antinociceptive action of morphine in mice, and R-PIA and NECA--in rats. 2-CADO did not affect the morphine action in the tests.     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

Interactions of ketamine, naloxone and morphine in the rat

The effect of naloxone on the ketamine-induced anesthesia and analgesia, and the development of tolerance to ketamine and the cross-tolerance to morphine (measured by an analgesic effect) were investigated in the rat. Ketamine produced a dose-dependent analgesia. Naloxone, 1 mg/kg, significantly inhibited analgesia induced by ketamine, 100 mg/kg, but even in a dose of 4 mg/kg it did not affect the duration of anesthesia. A chronic administration of ketamine (100 mg/kg twice a day (b.i.d.) for 7 days) resulted in the development of tolerance to analgesic effects of ketamine. The analgesic action of morphine was attenuated in rats receiving ketamine chronically, while the analgesic effects of ketamine were significantly potentiated in morphine-dependent rats. Ketamine, 25 mg/kg, significantly attenuated the withdrawal signs evoked by naloxone in morphine-dependent rats. The results corroborate the suggestion about the participation of the central opioid neurotransmission in the mechanism of ketamine action.     

Analgesic activity of anticancer agent suramin.

Suramin exhibited morphine-like analgesic activity in mice. It antagonized both thermal (hot-plate) and acetic acid-evoked writhing responses with ED50 values 1/100 and 1/68, respectively, that of morphine. The suramin- and morphine-induced hot-plate analgesia was suppressed by administration of 0.5 mg/kg naloxone. However, lower doses (5-30 micrograms/kg) of naloxone produced dose-related potentiation or suppression of suramin and morphine analgesia. This potentiation effect may be due to the inhibition of writhing by naloxone itself rather than be a direct antagonism of the morphine effect.     

Modulation of paracetamol antinociception by caffeine and by selective adenosine A2 receptor antagonists in mice

This study investigated the involvement of adenosine receptors in the interaction between paracetamol and caffeine in mice, using the adenosine A2A receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the adenosine A2B receptor antagonist 1-propyl-8-p-sulfophenylxanthine (PSB1115), in the tail immersion and hot-plate tests. Paracetamol (10-200 mg/kg) was antinociceptive in both tests, but, in contrast to previous studies, caffeine (10 mg/kg) was pronociceptive in the tail immersion test, and reduced the effects of paracetamol in both tests. SCH58261 (3 mg/kg) was antinociceptive in both tests and in its presence paracetamol (50 mg/kg) had no further effect. PSB1115 (10 mg/kg) had little effect alone but potentiated the effect of paracetamol (50 mg/kg) in the hot-plate test and abolished it in the tail immersion test. These results suggest that adenosine A2B receptors may be involved in the action of paracetamol in a pathway-dependent manner, and also support the existence of pronociceptive adenosine A2A receptors.     

Influence of prazosin and clonidine on morphine analgesia,tolerance and withdrawal in mice

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (₂-adrenoceptor agonist) and prazosin (₁-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another ₁-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of ₂-adrenoceptors in opioid actions, also ₁-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.     

Potentiation of morphine analgesia in rats given a single exposure to restraint stress immobilization.

Rats exposed to restraint stress and injected with morphine show significantly greater increases in tail-flick latency compared to unstressed rats. However, it is not necessary for rats to be restrained at the time of testing to elicit a potentiated analgesic response to morphine. We reported recently that analgesia induced by 4.0 mg/kg morphine was significantly potentiated in rats that had been restrained for only 1 h at 24 h prior to testing. One purpose of the present study was to extend this observation by determining the ability of a single exposure to restraint stress to potentiate dose-dependently morphine (0.0, 2.0, 4.0, and 8.0 mg/kg)-induced analgesia in the tail-flick test. A second purpose was to assess the generality of the phenomenon by determining whether prior restraint would potentiate the analgesic effect of morphine in another common analgesic assay, the hot-plate test. Dose- and time-course (20-120 min) curves for morphine were generated in rats exposed to one of two treatments: no restraint stress (NS) and a single exposure to 1 h of restraint (RS). Rats subjected to 1 h of restraint and tested 24 h later displayed significant time- and dose-dependent potentiation (1.3-2.0-fold) of morphine-induced analgesia compared to unstressed rats in both the tail-flick and hot-plate tests. These results demonstrate that a single period of restraint is sufficient to activate the mechanisms responsible for potentiation of morphine-induced analgesia and that the degree to which stress modified morphine's analgesia can be demonstrated using both the tail-flick and hot-plate assays.     

A long-form α-neurotoxin from cobra venom produces potent opioidindependent analgesia

AIM: In light of the antinociceptive activity of the short-chain neurotoxin, cobrotoxin, and other acetylcholine antagonists, the antinociceptive activity and mechanisms of cobratoxin (CTX), a long-chain postsynaptic alpha-neurotoxin, was investigated in rodent pain models. METHODS: CTX was administered intraperitoneally (30, 45, 68 microg/kg), intra-cerebral ventricularly (4.5 microg/kg) or microinjected into periaqueductal gray (PAG; 4.5 microg/kg). The antinociceptive action was tested using the hot-plate and acetic acid writhing tests in mice and rats. The involvement of the cholinergic system and opioid system in CTX-induced analgesia was examined by pretreatment of animals with atropine (0.5 mg/kg, im; or 10 mg/kg, ip) or naloxone (1 and 5 mg/kg, ip). The effect of CTX on motor activity was tested using the Animex test. RESULTS: CTX exhibited a dose-dependent analgesic action in mice as determined by both the hot-plate and acetic acid writhing tests. The peak effect of analgesia was seen 3 h after administration. In the mouse acetic acid writhing test, the intra-cerebral ventricular administration of CTX at 4.5 microg/kg (1/12th of a systemic dose) produced marked analgesic effects. Microinjection of CTX (4.5 microg/kg) into the PAG region did not elicit an analgesic action in rats in the hot-plate test. Atropine at 0.5 mg/kg (im) and naloxone at 1 and 5 mg/kg (ip) both failed to block the analgesic effects of CTX, but atropine at 10 mg/kg (ip) did antagonize the analgesia mediated by CTX in the mouse acetic acid writhing test. Acetylsalicylic acid (300 mg/kg) did not enhance the analgesic effects of CTX. At the highest effective dose of 68 microg/kg the neurotoxin did not change the spontaneous mobility of mice. CONCLUSION: CTX has analgesic effects, which are mediated in the central nervous system though not through the PAG. The central cholinergic system but not opioid system appears to be involved in the antinociceptive action of CTX.     

Ketamine-induced potentiation of morphine analgesia in rat tail-flick test: role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels

Ketamine is known to improve opioid efficacy, reduce postoperative opioid requirement and oppose opioid associated pain hypersensitivity and tolerance. However, the mechanisms underlying these beneficial effects are not clear. This study investigated the effects of ketamine at a non-analgesic dose (30 mg/kg, i.p.) on analgesia induced by morphine (2.5, 5.0, 7.5 mg/kg, s.c.), using rat tail-flick test as an animal model of acute pain. Further, the role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels was examined on the potentiating effect of ketamine. Male rats received morphine alone at 5.0 and 7.5 but not at 2.5 mg/kg showed a dose-related increase in tail-flick latencies. The combination of morphine and ketamine resulted in dose-related increase in morphine analgesia, both on the intensity as well as on duration. The ketamine-induced potentiation of morphine (7.5 mg/kg) analgesia was unaffected by glibenclamide (3 mg/kg, s.c.) and only partially blocked by yohimbine (2 mg/kg, i.p.), but more completely abolished by naloxone (2 mg/kg, i.p.). Both morphine (5.0 mg/kg) and ketamine (30 mg/kg) alone did not evoke catalepsy in rats but on combination produced a synergistic effect, which was however, abolished by naloxone pretreatment. In the open-field test, while morphine (5.0 mg/kg) caused a depressant effect, ketamine (30 mg/kg) enhanced the locomotor activity. Nevertheless, in combination potentiated the morphine's depressant effect on locomotion, which was also antagonized by naloxone. These results indicate that ketamine at a non-analgesic dose can potentiate morphine analgesia, induce catalepsy and cause locomotor depression, possibly involving an opioid mechanism. This potentiation, although favorable in acute pain management, may have some adverse clinical implications.     

Influence of tiagabine on the antinociceptive action of morphine, metamizole and indomethacin in mice

The influence of tiagabine at a dose of 3.2 mg/kg (single administration) and at a dose of 1.2 mg/kg (multiple administration - 10 days) on the antinociceptive effect of morphine (10 mg/kg), metamizole (500 mg/kg) and indomethacin (10 mg/kg - single dose and 1.4 mg/kg - multiple doses) was investigated in mice using the hot-plate and tail-flick tests. All drugs were injected intraperitoneally. Tiagabine was administered to mice 30 min before the analgesic drugs. Measurement of the reaction to a noxious stimulus was performed 60, 90 and 120 min after administration of tiagabine. The study was further conducted for 10 days with repeated drug doses. Tiagabine and morphine administered in single doses demonstrate an additive antinociceptive effect in the hot-plate test and a slightly synergistic effect in the tail-flick test. A single administration of tiagabine slightly increased the antinoceptive action of metamizole and indomethacin in both tests, but that effect is less pronounced than the antinociceptive action of tiagabine alone. Repeated administration of tiagabine with morphine abolishes the tolerance to morphine analgesia. Both single and repeated administration of tiagabine alone exerted the antinociceptive effect in the hot-plate test.     

Evidence for the involvement of central opioidergic systems in L-tyrosine methyl ester-induced analgesia in the rat

Intraperitoneal administration of L-tyrosine (used as methyl ester HCl) produced dose-dependent analgesia in male Sprague-Dawley rats as measured by the tail-flick test. The maximal analgesic response was obtained with 200 mg/kg dose of tyrosine. Administration of morphine also produced a dose-dependent analgesic response. Tyrosine in doses of 50 mg/kg or higher potentiated morphine-induced analgesia. The analgesic response of tyrosine (200 mg/kg) was antagonized by naloxone (1 mg/kg), an opiate antagonist. Subcutaneous administration of methyl naltrexone bromide (MRZ 2663 BR, 1 and 10 mg/kg) had no effect on tyrosine-induced analgesia. Intracerebroventricular injection of MRZ 2663 BR (1 and 10 micrograms/rat) effectively blocked tyrosine-induced analgesia. It is concluded that tyrosine-induced analgesia and its potentiation of analgesic response to morphine may be mediated via either the opiate receptors or activation of endogenous opioidergic systems of central origin.     

Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence

ZC88 is a novel non-peptide N-type voltage-sensitive calcium channel blocker synthesized by our institute. In the present study, the oral analgesic activity of ZC88 in animal models of acute and neuropathic pain, and functional interactions between ZC88 and morphine in terms of analgesia, tolerance and dependence were investigated. In mice acetic acid writhing tests, ZC88 (10-80 mg/kg) administered by oral route showed significant antinociceptive effects in a dose-dependent manner. The ED50 values of ZC88 were 14.5 and 14.3 mg/kg in male and female mice, respectively. In sciatic nerve chronic constriction injury rats, mechanical allodynia was ameliorated by oral administration of ZC88 at doses of 14, 28 and 56 mg/kg, suggesting ZC88 relieved allodynic response of neuropathic pain. When concurrently administered with morphine, ZC88 (20-80 mg/kg) dose-dependently potentiated morphine analgesia and attenuated morphine analgesic tolerance in hot-plate tests. ZC88 also prevented chronic exposure to morphine-induced physical dependence and withdrawal, but not morphine-induced psychological dependence in conditioned place preference model. These results suggested that ZC88, a new non-peptide N-type calcium channel blocker, had notable oral analgesia and anti-allodynia for acute and neuropathic pain. ZC88 might be used in pain relief by either application alone or in combination with opioids because it enhanced morphine analgesia while prevented morphine-induced tolerance and physical dependence.     

Modification of morphine-induced analgesia, tolerance and dependence by bromocriptine

The effect of two doses of bromocriptine, a dopamine agonist, on morphine-induced analgesia, tolerance and dependence was investigated in mice. Bromocriptine at doses of 0.04 and 0.08 mg/kg did not affect the baseline tail flick latency of mice but potentiated the morphine analgesia. Pretreatment of mice with 5 mg/kg of sulpiride, a D-2 antagonist, not only blocked the effect of 0.08 mg/kg of bromocriptine but also antagonized the morphine analgesia. Control animals given daily injections of 10 mg/kg of morphine rapidly developed tolerance to the analgesic effect. A combined treatment of bromocriptine with morphine given daily suppressed the development of tolerance to morphine analgesia. However, development of tolerance to morphine analgesia was not significantly modified in the animals treated daily with bromocriptine (0.08 mg/kg) plus sulpiride (5 mg/kg). Acute dependence was induced by the administration of 100 mg/kg of morphine. The administration of bromocriptine 30 min before naloxone significantly decreased the ED₅₀ value for naloxone for inducing jumping in mice. Coadministration of sulpiride and bromocriptine attenuated the ability of bromocriptine to potentiate the withdrawal syndrome of morphine dependence. The results indicate that bromocriptine potentiates morphine analgesia, suppresses the development of tolerance to morphine analgesia but exacerbates opiate withdrawal signs in morphine-dependent mice. These effects of bromocriptine appear to be mediated via D-2 receptors.     

Opioid mechanisms of some behavioral effects of ketamine

The effect of naloxone on the duration of sleep and on analgesia produced by ketamine, and on the development of tolerance and cross-tolerance with morphine to ketamine analgesic effects were investigated in mice. Ketamine produced a dose-dependent analgesia. Naloxone (4 mg/kg) significantly inhibited the analgesic effects of ketamine (40 mg/kg), but (given in a dose of 2 mg/kg) did not affect the duration of ketamine sleep. Chronic administration of ketamine (160 mg/kg twice daily for 7 days) resulted in a gradual shortening of ketamine sleep and in the development of tolerance to the analgesic action of ketamine. There also developed cross-tolerance between analgesic effects of morphine and ketamine. Ketamine (20 mg/kg) significantly inhibited symptoms of morphine abstinence produced in morphine-pelleted mice by naloxone administration or by pellet removal. The results suggest that at least some elements of the mechanism of action of ketamine and morphine may be common and related to the endogenous opioid system.     

Potentiation of opioid analgesia by the antidepressant nefazodone.

Nefazodone is a new antidepressant related structurally to trazodone. In addition to its activity in preclinical assays for antidepressant activity, nefazodone was a potent analgesic in the mouse hotplate assay. At 50 mg/kg s.c. nefazodone doubled baseline latencies in 40% of mice but was inactive in the tailflick test at any dose tested. The hotplate analgesia seen with nefazodone alone was not reversed by naloxone (10 mg/kg s.c.). In the tailflick assay, nefazodone (50 mg/kg s.c.) enhanced morphine's analgesic response, shifting morphine's ED50 from 3.1 mg/kg alone to 0.86 mg/kg in conjunction with nefazodone (P less than 0.05). Two days after implantation of a morphine pellet (75 mg) no mice remained analgesic in the tailflick assay. Administration of nefazodone (50 mg/kg s.c.) restored analgesia to 60% of mice (P less than 0.03). In selective analgesic assays, nefazodone enhanced mu 1, mu 2 and delta analgesia, but not kappa 1 or kappa 3 analgesia. Nefazodone did not affect morphine's LD50 and, in assays of gastrointestinal transit, nefazodone increased morphine's potency only slightly. In conclusion, nefazodone alone is analgesic in certain animal models. In conjunction with morphine, nefazodone potentiated analgesia with no effect on lethality and little effect on gastrointestinal transit, resulting in an increase in morphine's therapeutic index. These results suggest that nefazodone and similar agents may have a significant role in the management of pain.     

Monosodium glutamate and analgesia induced by morphine. Test-specific effects

Neonatal administration of monosodium glutamate (MSG) destroyed perikarya in the arcuate nucleus and median eminence, including those that contain met-enkephalin and beta-endorphin and it increased the density of opiate receptors in the midbrain. Treatment with glutamate decreased the analgesic response on the jump test following a 10 mg/kg dose of morphine, yet increased the analgesic response on the hot-plate test following 1 mg/kg dose of morphine. The present study demonstrated that changes in morphine-induced analgesia induced by glutamate varied as functions of the pain test and of gender. While males treated with glutamate displayed attenuated analgesia induced by morphine (2.5-15 mg/kg) on the jump test, jump thresholds of females treated with glutamate were potentiated after a 10 mg/kg dose of morphine and attenuated after a 15 mg/kg dose of morphine, relative to controls. In contrast, analgesia on the hot-plate test was potentiated in animals of both genders treated with glutamate after all doses of morphine. Changes in tolerance to morphine induced by glutamate also depended on the pain test and gender. While the peak analgesic response on the jump test did not occur until the fifth injection of morphine in all rats treated with glutamate, tolerance on the jump test was subsequently retarded in males treated with glutamate and accelerated in glutamate-treated females. Tolerance on the hot-palate test appeared not to be consistently affected by treatment with glutamate. Morphine-induced hyperthermia was initially decreased in rats treated with glutamate, but subsequently decreased in glutamate-treated males and increased in glutamate-treated females.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analgesic activity of pymadine

The analgesic effect of 4-aminopyridine (pymadine) was studied in experiments on rats and mice at thermal and chemical pain stimulation. Pymadine (1, 3 and 5 mg/kg) exerted the analgesic effect when administered alone and concomitantly with analgin and morphine at chemical pain stimulation. During thermal pain stimulation pymadine had the analgesic effect only at dosage of 5 mg/kg and potentiated the action of morphine given in doses of 3 and 5 mg/kg. The same doses of pymadine failed to influence changes in pain reaction induced by analgin at thermic pain stimulation.     

Comparison of the analgesic actions of THIP and morphine

The antinociceptive actions of intraperitoneally-administered 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and morphine were compared using three strains of mice. With the hot-plate assay, ED50 values for the action of THIP were about 4 mg/kg in OF1, CD1 and NMRI strains, whereas ED50 values for morphine varied among strains, being 6.8 mg/kg for OF1, 16.9 mg/kg for CD1, and about 29 mg/kg for NMRI mice; thus, the genetic control of the analgesic action of THIP appears to differ from that of morphine. The analgesic action of THIP in the hot-plate test was not blocked by naloxone, bicuculline, phentolamine or methysergide, but was partially reversed by a high dose of atropine, indicating that classic opiate-receptors, bicuculline-sensitive GABA-receptors, alpha-adrenoceptors and serotonin-receptors do not appear to mediate the action of THIP but that cholinergic receptors might be indirectly involved. THIP was about equipotent or more potent than morphine in the phenylbenzoquinone writhing test, evasion test, and traction test. Since the ED50 values for THIP in OF1 mice were similar for hot-plate, evasion and traction tests, the analgesic action of THIP might not be readily dissociated from its sedative or myorelaxant action.     

H1- and H2-histamine receptor blockers and opiate analgesia in mice

In this paper, the interactions between opiates and antihistaminic compounds, both H1- and H2-blockers, were studied. CD1 mice were used, treated with saline, morphine CHl (5 mg/kg), and 1 or 10 mg/kg of the H1-antihistaminics tripelennamine, chlorpheniramine, diphenhydramine and cyclizine and the H2-antihistaminics ranitidine and cimetidine, all compounds by s.c. route. Using the hot-plate test, it was observed that the two doses of tripelennamine and the higher doses of chlorpheniramine and cimetidine had antinociceptive activity. This increase on analgesia was also observed after chronic treatment with all H1-antihistaminics (10 mg/kg, 3 times daily for 4 days). When antihistaminics were administered with morphine, it was observed that only ranitidine (10 mg/kg) blocked opiate analgesia. On the other hand, previous administration of the opiate antagonist naloxone (1 mg/kg) blocked the antinociceptive action of tripelennamine and chlorpheniramine (10 mg/kg) in control mice. In morphine-dependent mice (by s.c. implantation of a 75-mg morphine pellet), a single injection of diphenhydramine or ranitidine blocked the analgesic action of morphine. Chronic administration of all antihistaminics did not modify morphine analgesia. These data are discussed in relation to the possible binding to the opioid receptors by antihistaminics and their facility in crossing the blood-brain barrier.