Antinociceptive Action Of Morphine Research Articles

Chronic sucrose intake reduces the antagonist effect of β-funaltrexamine on morphine-induced antinociception in female but not in male rats

Chronic ingestion of a sweet-tasting sucrose solution enhances the pain relieving actions of opioid agonists. These results, taken in conjunction with research demonstrating that sucrose stimulates the production and release of endogenous opioid peptides, have led to the hypothesis that the effects of palatable foods and fluids on pain sensitivity are mediated by the endogenous opioid system. To assess this hypothesis, two studies determined if chronic sucrose intake would block the antagonist effects of the μ-selective opioid antagonist β-funaltrexamine (β-FNA) on morphine-induced antinociception. Female and male Long-Evans rats were maintained on chow and water, or chow, water and a 32% sucrose solution. In Experiment 1, after four weeks on the diets, female rats received 0 or 10mg/kg (subcutaneously (sc)) β-FNA, while in Experiment 2, male and female rats received 0, 5 or 20 mg/kg β-FNA. Six days later, rats were tested for morphine-induced antinociception using the hot-water tail-withdrawal test. Morphine, administered using a cumulative dose regime (1.0, 3.0, 5.6, 10.0 and 31.0 mg/kg sc), led to dose-dependent increases in tail-withdrawal latencies in male and female rats. Males were more sensitive to the pain relieving properties of morphine than females. Sucrose intake increased, while β-FNA decreased the analgesic actions of morphine in males and females. β-FNA was less effective in blocking the antinociceptive actions of morphine in sucrose-fed female rats than in females fed only chow. In contrast, diet had minimal effects on responses to β-FNA in male rats.

Modulatory Role of Green Tea Extract on Antinociceptive Effect of Morphine in Diabetic Mice

Diabetic neuropathic pain is an important microvascular complication, and morphine has been demonstrated to be ineffective in this condition. Therefore the present study was designed to investigate the modulatory effect of green tea extract (GTE) on the decreased antinociceptive effect of morphine in diabetic mice. The tail withdrawal test was performed for measurement of the nociceptive threshold in both streptozotocin (STZ)-injected and control mice. Four weeks after administration of STZ, antinociception of morphine (5 mg/kg, s.c.) alone or in combination with GTE (25, 50, and 100 mg/kg, i.p.) was measured. Experimental diabetes markedly decreased the antinociceptive effect of morphine. The decrement in morphine response was significantly attenuated by GTE administration. When GTE (25 mg/kg) and a nitric oxide (NO) inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg, i.p), were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the antinociceptive action of morphine was significantly increased as compared with the GTE + morphine-treated diabetic group, but the increased antinociceptive action was significantly attenuated by administration of an NO precursor, L-arginine (100 mg/kg, i.p), instead of L-NAME. Plasma nitrite concentrations were estimated using the Griess reagent. Diabetes significantly increased the plasma nitrite levels that were attenuated by GTE administration. When GTE (25 mg/kg) and L-NAME (10 mg/kg, i.p) were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the plasma nitrite levels were significantly decreased as compared with the GTE + morphine alone-treated diabetic group, but the decreased plasma nitrite levels were significantly reversed by administration of L-arginine (100 mg/kg) instead of L-NAME. It may be concluded that increased NO formation may be responsible for the decreased antinociceptive effect of morphine in diabetic mice and that GTE restored the antinociceptive effect of morphine by inhibition of NO production. The results of the present study indicate the possibility of adding GTE as an adjuvant in the treatment of diabetic neuropathic pain.

The interaction of tetrahydroisoquinoline derivatives with antinociceptive action of morphine and oxotremorine in mice.

To extend our earlier data on synergistic action of tetrahydroisoquinolines and morphine, we have investigated the analgesic effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its 1-methyl-(1-MeTIQ) and N-methyl (N-MeTIQ) analogs on analgesia induced by morphine and oxotremorine. 1-MeTIQ and N-MeTIQ induced a moderate, delayed and prolonged analgesic action measured in the tail-flick test in CD-1 mice; 1-MeTIQ and TIQ prolonged the opiate (morphine, 2.5 mg/kg i.p.) analgesia while TIQ and N-TIQ potentiated cholinergic (oxotremorine, 0.02 mg/kg i.p.) analgesia. The involvement of the opioid and noradrenergic systems in this effect is discussed.

Effects of morphine on formalin-induced nociception in rats

This study focused on the antinociceptive action of morphine in the formalin test in rats. Formalin-induced behaviour is characterised by two phases relevant to acute and tonic pain. Morphine (1–6 mg/kg) was administered systemically before or after the early phase, and its ability to affect the late phase was investigated. Inhibitory effects of morphine (3 mg/kg) injected immediately after the early phase were significantly stronger (32±9%) compared to the preemptive administration (84±29%, relative to saline-treated controls, 5% formaldehyde). It appears that some neural and/or behavioural changes during the early phase limit effects of morphine on the late phase. Furthermore, manipulation of stimulation intensity (2% vs. 5% formaldehyde) significantly affected the ability of morphine (3 mg/kg) to suppress early (55±7% and 76±10%, respectively) but not late phase of formalin-induced behaviours. These results agree with the previous demonstrations on the effects of acute nociceptive stimulation intensity on analgesic potency of opiate drugs. Thus, the present study revealed two factors that affect the potency of morphine in formalin test: administration regimen and formalin concentration.

Altered pain sensitivity and morphine-induced anti-nociception in mice lacking CCK2 receptors.

Cholecystokinin (CCK) interacts with the endopioid system in the regulation of various physiological functions, including the control of pain sensitivity, motor activity and emotional behaviour. The aim of the present work was to study the pain sensitivity, morphine-induced antinociception and density of opioid receptors in mice lacking CCK(2) receptors. Plantar analgesia and hotplate tests were used to evaluate pain sensitivity and morphine-induced antinociception. The parameters of opioid receptors were analysed by using [(3)H]-diprenorphine binding. In the plantar analgesia test the latency of hind paw withdrawal was significantly increased in CCK(2) receptor deficient mice compared to wild-type (+/+) littermates. The treatment with saline reversed the reduced pain sensitivity in heterozygous (+/-) and homozygous (-/-) mice. The administration of morphine (1 mg/kg) induced a significantly stronger antinociceptive effect in homozygous (-/-) mice compared with wild-type (+/+) animals. In the hotplate test, only homozygous (-/-) mutant mice displayed the delayed latency of hind paw licking/shaking in comparison with wild-type (+/+) mice. The injection of saline and isolation of mice for 30 min reversed the delayed response in homozygous (-/-) mice. However, in this test, the anti-nociceptive action of morphine (5-10 mg/kg) in mutant mice did not differ from that in wild-type (+/+) littermates. By contrast, the jump latency was decreased in both homozygous (-/-) and heterozygous (+/-) mice in the hotplate test. The increased density of opioid receptors was established in the striatum of homozygous (-/-) mice. It is apparent that the targeted mutagenesis of the CCK(2) receptor gene has different effects on the sensitivity of opioid receptors in various brain structures. This is a probable reason for the altered pain sensitivity and morphine-induced antinociception in mutant mice compared to wild-type (+/+) littermates.

Increases in the release and metabolism of serotonin in nucleus parafascicularis thalami following systemically administered morphine in the rat

The effects of systemically administered morphine on the release and metabolism of serotonin (5-HT) in nucleus parafascicularis thalami were evaluated using in vivo microdialysis. The extracellular concentration of 5-HT and its major metabolite 5-hydroxyindoleacetic acid were increased in a dose-dependent manner following the subcutaneous administration of 2.5 and 5 mg/kg morphine sulfate. These results are consistent with findings that the antinociceptive action of morphine is partially mediated through the action of 5-HT within nucleus parafascicularis.

The effects of NMDA receptor antagonists on acute morphine antinociception in mice.

Antagonists of the N-methyl- d-aspartate (NMDA) receptor complex inhibit the development of tolerance to antinociceptive effects of morphine and upon acute administration, influence morphine antinociceptive activity. The analysis of numerous studies investigating acute interaction between NMDA receptor antagonists and morphine in mice indicate a variety of procedural differences and reveal that these compounds may potentiate, attenuate and produce no effect on morphine antinociception. The conditions responsible for such conflicting experimental outcome of acute interaction remain unclear. It appears that the effects of NMDA receptor antagonists on morphine tolerance are not causally related to their acute effects on morphine antinociception.

Acamprosate decreases the induction of tolerance and physical dependence in morphine-treated mice

The effects of acamprosate, a drug thought to interact with N-methyl- d-aspartate (NMDA) receptors in the central nervous system (CNS), were examined on the antinociceptive action of morphine, induction of tolerance to and physical dependence on morphine, and expression of the abstinence syndrome to the opiate in mice. For the induction of tolerance and dependence, morphine (300 mg/kg) was administered by means of a slow-release preparation. Single doses of acamprosate (50, 100, 200, or 400 mg/kg) administered 30 min before a test dose of morphine did not change the antinociceptive effects of morphine in drug-naive mice. The drug was also administered in repeated doses (50, 100, 200, or 400 mg/kg, 30 min before and 12 and 24 h after the priming dose of morphine) in order to evaluate its effects on the induction of tolerance; all doses assayed, except the 400 mg/kg, did not affect the intensity of tolerance. The acute administration of acamprosate (50, 100, 200, or 400 mg/kg, injected 30 min before naloxone to morphine-pretreated mice) did not affect the intensity of the abstinence behavior. However, the repeated administration of 100 mg/kg of acamprosate (30 min before and 12 and 24 h after the priming dose of morphine) decreased the intensity of physical dependence. The results of these studies suggest that acamprosate may have modulatory effects on glutamatergic neurotransmission participating in the adaptive mechanisms induced by chronic morphine treatment.

The spinal antinociceptive effect of FR140423 in mice Involvement of the descending noradrenergic and serotonergic systems

In this study, we investigated the role of descending monoaminergic systems in the antinociceptive activity of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methyl sulfinyl)phenyl]pyrazole, by using the tail-pinch test in mice and various monoamine depletors. The antinociceptive effects of FR140423 given p.o. and i.t. with ED 50 values of 22 mg/kg and 3.5 μg/mouse, respectively, in the tail-pinch test were antagonized by reserpine, 6-hydroxydopamine plus nomifensine, and p-chlorophenylalanine treatment, whereas the antinociceptive action of morphine in this assay was attenuated by reserpine and 6-hydroxydopamine plus nomifensine but not by p-chlorophenylalanine treatment. These results suggest that both descending noradrenergic and serotonergic systems are involved in the antinociceptive activity of spinally and systemically administered FR140423 against mechanical noxious stimuli. The mechanisms underlying the suppressive action of FR140423 on the nociceptive response may differ from those of morphine in mice.

Wheel running attenuates the antinociceptive properties of morphine and its metabolite, morphine-6-glucuronide, in rats

Recent work has shown that chronic exercise is associated with a reduction in the pain-relieving actions of opioid drugs in experimental animals. To determine whether this reduction represents an interaction between exogenously administered opioids and the endogenous opioid system, or is the result of altered drug pharmacokenitics, the antinociceptive actions of morphine and its metabolite, morphine-6-glucuronide (M6G), were compared in active and inactive female Long–Evans rats. Active animals were housed in running wheels and inactive animals in standard laboratory cages for 3 weeks preceding determinations of antinociception using the tail-flick test. At the end of the 3-week period, active rats were running the equivalent of 9–11 km a day. Antinociceptive responses, determined following subcutaneous injections of either morphine (0.625–20 mg/kg) or M6G (0.3–10.0 mg/kg), were significantly reduced in active rats relative to inactive rats. This reduction was manifested by both a lower magnitude of antinociception, and a shorter duration of antinociception after drug administration in active compared to inactive rats. This reduction was not associated with alterations in the estrous cycle or with differences in body weight between the active and inactive animals. The present results support the hypothesis that cross-tolerance develops between endogenous opioid peptides released in response to exercise and exogenously administered opioid drugs.

Spinal effect of the cholecystokinin-B receptor antagonist CI-988 on hyperalgesia, allodynia, and morphine-induced analgesia in diabetic and mononeuropathic rats. (Laboratoire de Physiologie, Clermont-Ferrand Cedex 1, France) Pain 2000;88:15-22.

This study examined the effect of intrathecal CI-99, an antagonist of the CCK-B receptors, on mechanical hyperalgesia and allodynia in normal, mononeuropathic and diabetic rats. The effect of the combination of CI-988 and IV morphine on mechanical hyperalgesia in diabetic and mononeuropathic rats was evaluated using isobolographic analysis. Although ineffective in normal rats, CI-988 induced antinociceptive effects in diabetic and mononeuropathic rats, suggesting an involvement of the CCKergic system in neurogenic pain conditions. The combination of CI-988 and morphine showed a superadditive interaction in the diabetic rats only. In addition, CI-988 exhibited a weak antiallodynic effect in mononeuropathic rats, and no antiallodynic effect in diabetic rats. These results show the CCK-B receptor blockade-mediated antinociceptive effects and reveal the antinociceptive action of morphine in diabetic rats after CCKergic system inhibition.

Uncompetitive NMDA receptor antagonists potentiate morphine antinociception recorded from the tail but not from the hind paw in rats

We investigated the effects of pretreatment with low-affinity, uncompetitive NMDA receptor antagonists on morphine-induced antinociception in rats using the same intensity of thermal stimulus applied to the tail and the paws. Similar baseline responses to thermal stimuli of the same intensity were recorded from tails and hind paws. However, morphine produced equal antinociception from the tail and hind paw when used at doses of 2.5 and 6 mg/kg, respectively. These doses were used in further experiments. Thirty minutes before morphine, rats were administered the NMDA receptor antagonists dextromethorphan (2.5–30 mg/kg), memantine (2.5–15 mg/kg) and MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) (1.25–10 mg/kg). All three compounds significantly and dose-dependently potentiated morphine-induced antinociception recorded from the tail. However, none of these NMDA receptor antagonists affected morphine antinociception recorded from the paw. These findings suggest that low-affinity NMDA receptor antagonists modulate differently morphine antinociceptive activity recorded from the tail and hind paws.

The nociceptin/orphanin FQ receptor antagonist, [Nphe1]NC(1-13)NH2, potentiates morphine analgesia.

Nociceptin/orphanin FQ (NC) and its receptor (OP4) represent a novel peptide/receptor system which has been implicated in the regulation of various central functions, including pain. The aim of the present study was to explore the involvement of the endogenous NC/OP4 system in the modulation of opioid analgesia using the selective OP4 receptor antagonist [Nphe1]NC(1-13)NH2. Experiments were performed in mice exposed to acute as well as chronic treatment with morphine. [Nphe1]NC(1-13)NH2, injected i.c.v. at 30 nmol, strongly potentiated the analgesic effect of supraspinal morphine (1 nmol, i.c.v.) while it only slightly increased the antinociceptive activity of morphine given systemically (5 mg/kg, s.c.). [Nphe1]NC(1-13)NH, (30 nmol, i.c.v.) also potentiated morphine analgesia in mice made tolerant to the opiate (30 mg/kg/day for 4 days). These findings implicate the endogenous NC signaling as a modulator of morphine analgesia and tolerance.

Amygdaloid-thalamic interactions mediate the antinociceptive action of morphine microinjected into the periaqueductal gray.

The bilateral administration of the serotonin receptor antagonist methysergide (2.5 microg, 5 microg, and 10 microg) into either the central nucleus of the amygdala (ACe) or nucleus parafascicularis thalami (nPf) produced dose-dependent inhibition of the antinociceptive action of ventrolateral periaqueductal gray (vPAG)-administered morphine. Unilateral administration of these doses of methysergide into either the ACe or nPf had no effect on morphine-induced antinociception. However, the combined unilateral administration of these doses of methysergide into the ACe and nPf produced dose-dependent inhibition of morphine antinociception that was identical to that observed after its bilateral administration into either site. This latter finding is interpreted as evidence that a functional interaction between the ACe and nPf supports the antinociceptive action of morphine administered into the vPAG.

Amygdaloid–thalamic interactions mediate the antinociceptive action of morphine microinjected into the periaqueductal gray.

Amygdaloid–thalamic interactions mediate the antinociceptive action of morphine microinjected into the periaqueductal gray.

Morphine antinociception is enhanced in mdr1a gene-deficient mice.

Previous studies have suggested that P-glycoprotein (P-gp) modulates opioid antinociception for selected mu-and delta-agonists. This study was undertaken to assess morphine antinociception in mice lacking the mdr1a gene for expression of P-gp in the CNS. Morphine (n = 4-5/group) was administered as a single s.c. dose to mdr1a(-/-) mice (3-5 mg/kg) or wild-type FVB controls (8-10 mg/kg). Tail-flick response to radiant heat, expressed as percent of maximum response (%MPR), was used to determine the antinociceptive effect of morphine. Concentrations in serum, brain tissue, and spinal cord samples obtained immediately after the tail-flick test were determined by HPLC with fluorescence detection. Parallel experiments with R(+)-verapamil, a chemical inhibitor of P-gp, also were performed to further investigate the effect of P-gp on morphine-associated antinociception. Morphine-associated antinociception was increased significantly in the mdr1a(-/-) mice. The ED50 for morphine was > 2-fold lower in mdr1a(-/-) (3.8+/-0.2 mg/kg) compared to FVB (8.8+/-0.2 mg/kg) mice. However, the EC50 derived from the brain tissue was similar between the two mouse strains (295 ng/g vs. 371 ng/g). Pretreatment with R(+)-verapamil produced changes similar to those observed in gene-deficient mice. P-gp does not appear to affect morphine distribution between spinal cord and blood, as the spinal cord:serum morphine concentration ratio was similar between gene-deficient and wild-type mice (0.47+/-0.03 vs. 0.56+/-0.04, p>0.05). The results of this study are consistent with the hypothesis that P-gp attenuates the antinociceptive action of morphine by limiting the brain:blood partitioning of the opioid.

Riluzole decreases the abstinence syndrome and physical dependence in morphine-dependent mice

The effects of the antiglutamatergic agent, riluzole, were examined on the antinociceptive action of morphine, on the induction of physical dependence, and on the expression of the abstinence syndrome to the opiate in mice. Morphine was administered as a single dose (200 mg/kg) of a slow-release preparation. Acute and chronic administration of riluzole decreased the analgesic response to morphine, the intensity of abstinence behavior (administered 30 min before a dose of naloxone), and the development of physical dependence (repeatedly administered during the period of chronic morphine treatment).

Differential contributions of medullary, thalamic, and amygdaloid serotonin to the antinociceptive action of morphine administered into the periaqueductal gray: a model of morphine analgesia.

The relative contribution of serotonin (5HT) neurotransmission within the medulla (rostral ventromedial medulla) and forebrain (amygdaloid central nucleus and nucleus parafascicularis thalami) to the antinociceptive action of morphine microinjected into the ventrolateral periaqueductal gray (vPAG) was evaluated. The 5HT receptor antagonist methysergide was microinjected into the medulla, forebrain, (or both) after injection of morphine into the vPAG. The contribution of 5HT to the antinociceptive action of morphine was observed to depend on (a) the dose of morphine administered into the vPAG, (b) the site(s) at which methysergide was administered, and (c) the level of the neuraxis at which the behavioral assay was organized. Results of the present study were combined with those of previous studies from this laboratory and presented as a model of the mechanisms by which morphine administered into the vPAG generates its antinociceptive action.

Differential contributions of medullary, thalamic, and amygdaloid serotonin to the antinociceptive action of morphine administered into the periaqueductal gray: A model of morphine analgesia.

Differential contributions of medullary, thalamic, and amygdaloid serotonin to the antinociceptive action of morphine administered into the periaqueductal gray: A model of morphine analgesia.

The effects of piracetam on morphine-induced amnesia and analgesia: The possible contribution of central opiatergic mechanisms on the antiamnestic effect of piracetam

The involvement of opiatergic mechanisms on the antiamnestic effects of piracetam was investigated in mice. First, the effects of piracetam and naloxone on the amnesia induced by scopolamine, electroconvulsive shock and morphine were evaluated by using elevated plus maze apparatus. Second, the effects of electroconvulsive shock and piracetam on the antinociceptive action of morphine were tested by means of radiant heat tail-flick experiment. Piracetam and naloxone reversed the drug- or electrically-induced amnestic effects. On the other hand, electroconvulsive shock treatment enhanced the antinociceptive effect of morphine while piracetam decreased the same activity. These results suggest an important role of the opiatergic system on the learning and memory process as well as on the antiamnestic effect of piracetam.