Effects of morphine in rats withdrawn from repeated nifedipine administration

The effects of withdrawal from repeated nifedipine treatment on morphine-induced analgesia, hyperthermia and catalepsy as well as on cerebral [3H]nitrendipine binding and on morphine-induced changes in striatal and limbic dopamine and 5-hydroxytryptamine metabolism were studied in rats. Repeated administration of nifedipine (5 mg/kg i.p., twice daily for 14 days) decreased [3H]nitrendipine binding in several brain areas of the rats at 24 h after the last dose but did not change the nociceptive response or rectal temperature of the animals. Further, the antinociceptive potency of acute morphine (2.5 mg/kg s.c.) was significantly reduced in rats withdrawn for 24 h from repeated nifedipine treatment. However, withdrawal from repeated nifedipine treatment failed to affect either the hyperthermia induced by this dose of morphine or the catalepsy and the elevation of dopamine or 5-hydroxytryptamine metabolites induced by 15 mg/kg of morphine. Taken together, these data show that withdrawal from repeated treatment with dihydropyridine calcium channel antagonists selectively reduces the effects of opioids on the nociceptive response.     

Pro-Leu-Gly-NH? serves as a conditioned stimulus in the acquisition of conditioned tolerance.

The effect of Pro-Leu-Gly-NH? (MIF) on the acquisition of tolerance to morphine-induced antinociception and its efficacy as a cue predictive of morphine administration was examined. Daily administration of MIF prior to morphine injection did not attenuate the acquisition of tolerance to the antinociceptive properties of morphine, as measured by the latency to hindpaw lick in a hot-plate test of analgesia. When the animals were tested 72 hrs later without MIF pretreatment, they appeared to lose tolerance, as indicated by longer latencies to paw lick. These data suggest that in some situations MIF may interfere with the acquisition of tolerance by acting as a cue that reliably predicts the antinociceptive properties of morphine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Early endoscopic realignment as primary therapy for complete posterior urethral disruptions

Circadian changes in the interactions between L-NG-nitroarginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and morphine-induced antinociception were investigated by the mouse hot-plate test. Both the basal pain sensitivity and morphine-induced analgesia undergo significant 24 h variations. L-NAME (40 mg/kg, i.p.) alone did not show any antinociceptive activity, but potentiated morphine-induced analgesia when combined with morphine at all injection times. In terms of percentage absolute potentiation (%AP), L-NAME dramatically augmented the analgesic effect of morphine in the late dark period at 19 hours after lights on (HALO). It is concluded that nitric oxide (NO) is involved in the modulation of the analgesic effect of morphine; thus, the L-NAME and morphine combination might be beneficial in alleviating pain.     

ACEA-1328, an NMDA receptor antagonist, increases the potency of morphine and U50,488H in the tail flick test in mice

The effect of 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was examined on opioid-induced antinociception in the tail flick test. Swiss Webster mice were injected with ACEA-1328 either alone or in combination with morphine or (+/-)-trans-U-50488 methanesulfonate (U50,488H), a mu- and a kappa-opioid receptor agonist, respectively, and tested for antinociception. Systemic administration of ACEA-1328 alone increased the tail flick latencies with an ED50 of approximately 45 mg kg-1. Concurrent administration of ACEA-1328 with morphine, or U50,488H, at doses that did not affect tail flick latencies, potentiated the antinociceptive effect of the opioid analgesics and vice versa. Naloxone, an opioid receptor antagonist, while not modifying the effect of ACEA-1328, did block the augmentation, suggesting that opioid receptors might be involved in the latter effect. 5-Aza-7-chloro-4-hydroxy-3-(m-phenoxyphenyl)quinoline-2(1H)-one (ACEA-0762), a selective NMDA receptor/glycine site antagonist, also showed enhancement of the antinociceptive effect of morphine and U50,488H. However, concurrent administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzol[f]quinoxaline (NBQX), a selective non-NMDA receptor antagonist, with morphine did not alter the antinociceptive potency of the opioid analgesic. Overall, the data suggest that ACEA-1328 may increase the potency of the opioid analgesics by antagonising the glycine site associated with the NMDA receptor.     

HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic hemochromatosis

The antinociceptive actions of morphine incorporated into an injectable chitosan-based gel were investigated in rats. Subcutaneous administration of 4.8 mg/kg morphine sulphate in a gel composed of N,O-carboxymethylchitosan (NOCC) and chitosan resulted in significant antinociception within 10 min that was maximal at 60 min and persisted for 6 h. In contrast, the same dose of morphine sulphate injected in sterile saline produced maximal responses at 30 min but only persisted for 2 h. NOCC/chitosan gel was easily injectable using a 22 guage needle and appears stable in long-term storage. No local or systemic adverse effects other than morphine-induced sedation were observed either at the time of injection or during the subsequent 48 h. We conclude that gels composed of chitosan and chitosan derivatives are effective matrices for sustained-release formulations of opioid analgesics capable of providing long-lasting antinociception.     

Effect of morphine-induced catalepsy, lethality, and analgesia by a benzodiazepine receptor agonist midazolam in the rat

Previously we have shown that intrathecal administration of midazolam can increase or decrease morphine-induced antinociception, depending upon relative concentration of these drugs by modulating spinal opioid receptors, and it also can inhibit morphine-induced tolerance and dependence in the rat. Now we report that midazolam also influences catalepsy, lethality, and analgesia induced by morphine in the rat. In the acute treatment, animals were first treated with saline or midazolam (0.03 to 30.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (1.0 to 100.0 mg/kg, b.wt., SC). The catalepsy was measured 60 min after the second injection and lethality was checked after 24 h. Midazolam injection increased the morphine-induced catalepsy and lethality. In the chronic treatment, animals were injected with two injections daily for 11 days. The first injection consisted of saline or midazolam (0.03 to 3.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (10.0 mg/kg, b.wt., IP) was given. Lethality, antinociception, and body weight were measured. Chronic morphine treatment also increased lethality in a dose-dependent manner. Chronic treatment with midazolam and morphine increased the antinociception on day 11, as measured in the tail-flick and hot-plate tests. Midazolam administration also prevented the morphine-induced weight loss. These results suggest a strong interaction between midazolam and morphine in altering catalepsy, lethality, and analgesia in rat.     

Prior morphine exposure enhances ibogaine antagonism of morphine-induced dopamine release in rats

The present study examines the effect of prior morphine exposure on ibogaine antagonism of morphine-induced dopamine release. Female Sprague-Dawley rats were pretreated once a day for 2 days with morphine (20 mg/kg, i.p.) or saline and given a low dose of ibogaine (10 mg/kg, i.p.) or saline 5 hr after the last morphine or saline injection. Nineteen hours later, rats (awake and freely moving) were challenged with morphine (5 mg/kg, i.p.), and dopamine and its metabolites were monitored in the striatum and nucleus accumbens using in vivo microdialysis. Neither saline pretreatment, morphine pretreatment, nor ibogaine alone altered morphine-induced increases in extracellular dopamine and dopamine metabolites in either structure. However, when morphine pretreatment was combined with ibogaine, the morphine-induced elevation of dopamine, but not of metabolites, was completely blocked. These data suggest that prior morphine exposure enhances an opioid antagonist action of ibogaine on dopaminergic systems and that prior drug exposure may be a clinically significant determinant of ibogaine efficacy and/or potency in the treatment of opioid addiction.     

Spinal cholinergic and monoamine receptors mediate the antinociceptive effect of morphine microinjected in the periaqueductal gray on the rat tail, but not the feet

The antinociceptive effects of morphine (5 micrograms) microinjected into the ventrolateral periaqueductal gray were determined using both the tail flick and the foot withdrawal responses to noxious radiant heating in lightly anesthetized rats. Intrathecal injection of appropriate antagonists was used to determine whether the antinociceptive effects of morphine were mediated by alpha 2-noradrenergic, serotonergic, opioid, or cholinergic muscarinic receptors. The increase in the foot withdrawal response latency produced by microinjection of morphine in the ventrolateral periaqueductal gray was reversed by intrathecal injection of the cholinergic muscarinic receptor antagonist atropine, but was not affected by the alpha 2-adrenoceptor antagonist yohimbine, the serotonergic receptor antagonist methysergide, or the opioid receptor antagonist naloxone. In contrast, the increase in the tail flick response latency produced by morphine was reduced by either yohimbine, methysergide or atropine. These results indicate that microinjection of morphine in the ventrolateral periaqueductal gray inhibits nociceptive responses to noxious heating of the tail by activating descending neuronal systems that are different from those that inhibits the nociceptive responses to noxious heating of the feet. More specifically, serotonergic, muscarinic cholinergic and alpha 2-noradrenergic receptors appear to mediate the antinociception produced by morphine using the tail flick test. In contrast, muscarinic cholinergic, but not monoamine receptors appear to mediate the antinociceptive effects of morphine using the foot withdrawal response.     

The "Wallstent": a new stent for the treatment of urethral strictures

Morphine or morphine-6-glucuronide either alone or in combination with morphine-3-glucuronide was administered intrathecally to rats. Antinociceptive effects were evaluated with the tail flick and the hot plate tests. Motor function was tested using the rotarod test. Estimated ED50 from the dose-response curves for morphine and morphine-6-glucuronide showed about a 30 times more potent antinociceptive effect of morphine-6-glucuronide compared with morphine. Morphine-3-glucuronide had no antinociceptive effect. Simultaneous administration of morphine-3-glucuronide 5.0 micrograms did not show any significant effect on antinociception induced by morphine 1.0 microgram or morphine-6-glucuronide 0.05 microgram.     

The antinociceptive effects of branched-chain amino acids: evidence for their ability to potentiate morphine analgesia

The effect of branched-chain amino acids (BCAA) on pain threshold was studied in rats. Nociception was induced by the hot-plate analgesia meter, a method measuring supraspinally organized pain responses. After a single intravenous injection of BCAA (320 mg/kg), the percent change in latency time to the pain response significantly increased by 19% in 60 min, and by 22% in 75 min (p < 0.005), as compared to an injection of an equal volume of a standard concentration of an amino acid solution or physiological saline. Subsequently, we studied the interaction of BCAA with opioid-type analgesia. In combination with intravenously injected morphine (3 mg/kg), BCAA significantly potentiated and prolonged the action of morphine using the hot-plate test. From 5 min after morphine injection, the latencies to a pain response were markedly higher with the combination of BCAA and morphine (+80% and +89% at 5 min after morphine injection, if BCAA was administered 45 or 60 min prior to morphine injection, respectively) when compared with the effect of morphine alone (+13% at 5 min; p < 0.005). BCAA demonstrated analgesic effects, which, in combination with morphine, potentiated and prolonged the antinociceptive action of morphine. BCAA may represent a new adjunct treatment modality for acute and chronic pain, and give us further insight into the mechanisms of pain control.     

Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay

The antinociceptive effects of mu and kappa agonists were examined after the systemic administration of the opioid antagonists nor-binaltorphimine (nor-BNI) and naloxone in the late response or tonic nociceptive phase of the mouse formalin assay. Initially, SC morphine (ED50, 0.97 mg/kg), racemic U-50488H (ED50, 0.79 mg/kg), (-)U-50488 (ED50, 0.41 mg/kg), and another agonist PD 117,302 (ED50, 0.28 mg/kg) were found to produce graded increases in the level of antinociception as measured by this procedure; naloxone, administered immediately before morphine and U-50488H, antagonized their antinociceptive actions. The effects of morphine and U-50488H then were evaluated 10 min to 96 h after the administration of nor-BNI. Subcutaneous nor-BNI at 30.0 mg/kg, but not at 3.0 or 10.0 mg/kg, attenuated the antinociceptive effects of morphine and U-50488H when the interval separating nor-BNI and the agonists was kept constant at 1 h. Time-course analysis of the effects of combinations of nor-BNI with morphine led to irregular findings: 10.0 mg/kg of nor-BNI lessened the effects of morphine (2.0 mg/kg) if the dosing interval was 10 min, whereas 30.0 mg/kg of nor-BNI attenuated the effects of morphine (2.0 mg/kg) if the dosing interval was 1 or 4 h; 10.0 mg/kg of nor-BNI also diminished the antinociceptive effects of U-50488H (1.7 mg/kg) only if the interval spacing the two drugs was 24 h. In comparison, a threefold higher dose of nor-BNI (30.0 mg/kg) reduced the effects of U-50488H (1.7 mg/kg) if the interval was 1 h or more. In these latter experiments, the antagonist effects of SC nor-BNI (30.0 mg/kg) were evident up to 96 h posttreatment. These results show that the mu opioid antagonist activity of nor-BNI is variable and that the kappa opioid antagonist selectivity of nor-BNI is a function of dose and treatment interval and is long-lasting even after systemic administration.     

Inhibition of cleavage by restriction endonucleases due to modifications induced in SV40 DNA by methyl methanesulfonate

Partially decorticated rats were tested for their response to nociceptive stimulation in the formalin and tail flick tests, and for the effect of morphine on these responses and on motor activity. Undrugged rats showed vigorous responses to nociceptive stimulation in both tests, and exhibited the typical biphasic time course of pain in the formalin test. Morphine 4 and 8 mg/kg produced dose-dependent analgesia in both tests in sham operated rats, and in rats with lesions that removed all or part of the cortex from the midline to the rhinal fissure (excluding the occipital cortex). In rats with lesions that extended deep into the piriform cortex and damaged the amygdala morphine analgesia was eliminated or attenuated. These and other recent findings suggest that analgesia in the formalin test depends on ascending connections to the forebrain, probably the amygdala.     

Dietary self-selection in chronically insulin-treated golden hamsters.

24 adult male golden hamsters were maintained on either Purina Rat Chow (chow group) or a self-selection diet consisting of high-protein chow, pure carbohydrate, and pure fat (choice group). Ss were injected for 12 consecutive days with either long-acting insulin (20, 60, and 100 U/kg for 4 days each) or physiological saline. Insulin-injected Ss under both dietary conditions increased their total caloric consumption by up to 33% and gained significantly more weight than saline-injected controls. Choice Ss increased their fat intake in response to the 60 and 100 U/kg dose of insulin, but carbohydrate and protein consumption increased only in response to the 100 U/kg dose. Choice Ss derived approximately 65% of the excess calories ingested during insulin administration from fat but only 20% from carbohydrate and 15% from protein. Results are related to those previously observed in other species. (17 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats

The effects of acute and chronic administration of cocaine on the antinociception and tolerance to the antinociceptive actions of mu-(morphine), kappa-(U-50,488H), and delta-([D-Pen2,D-Pen5]enkephalin; DPDPE), opioid receptor agonists were determined in male Swiss-Webster mice. Intraperitoneal injection of 40 mg/kg of cocaine by itself produced weak antinociceptive response as measured by the tail-fick test but the lower doses were ineffective. Administration of morphine (10 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (10 microg/mouse, ICV) produced antinociception in mice. Cocaine (20 mg/kg) potentiated the antinociceptive action of morphine and DPDPE but had no effect on U-50,488H-induced antinociception. Administration of morphine (20 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (20 microg/mouse, ICV) twice a day for 4 days resulted in the development of tolerance to their antinociceptive actions. Tolerance to the antinociceptive actions of morphine and U-50,488H was inhibited by concurrent treatment with 20 or 40 mg/kg doses of cocaine; however, tolerance to the antinociceptive action of DPDPE was not modified by cocaine. It is concluded that cocaine selectively potentiates the antinociceptive action of mu- and delta- but not of the kappa-opioid receptor agonist. On the other hand, cocaine inhibits the development of tolerance to the antinociceptive actions of mu- and kappa- but not of delta-opioid receptor agonists in mice.     

Inhibition of morphine-induced tolerance and dependence by a benzodiazepine receptor agonist midazolam in the rat

We investigated whether midazolam administration influenced morphine-induced antinociception and tolerance and dependence in the rat. Antinociception was assessed by the tail-flick (TF) and the hot-plate test (HP 52 degrees C). Morphine tolerance developed after daily single injections of morphine for 11 days. The effect of midazolam on morphine-induced antinociception and tolerance was assessed by giving daily injections of various doses of midazolam for 11 days. The first injection of saline or midazolam was given intraperitoneally and 30 min later morphine (10 mg/kg body weight) was administered subcutaneously. Antinociception was monitored by measuring TF and HP latencies 60 min after the second injection. Midazolam was injected at four different concentrations: 0.03, 0.1, 0.3, and 3 mg/kg body weight. Chronic administration of morphine resulted in the development of tolerance to antinociception in both TF and HP tests, with rats exhibiting baseline antinociception on Day 9. Animals treated with midazolam alone showed little antinociception on Days 3-9. However, midazolam administration in morphine-treated animals attenuated morphine-induced tolerance to antinociception on Days 1-11 as measured by the tail-flick test. Midazolam also decreased the jumping behavior following naloxone injections in morphine-dependent rats. These results suggest that midazolam may prolong the effects of morphine by delaying morphine-induced development of tolerance to antinociception. Midazolam also attenuated a decrease in weight gain induced by chronic injections of morphine.     

Further evidence that nitric oxide modifies acute and chronic morphine actions in mice

The effects of the nitric oxide (NO) synthase inhibitor, N(omega)-nitro-L-arginine (L-NNA, 2.5-10 microg i.c.v.), and the NO synthesis precursor, L-arginine (L-Arg, 2.5-10 microg i.c.v.), on morphine-induced analgesia, and on morphine-induced tolerance and dependence were examined in mice. Administration of L-NNA diminished the morphine-induced analgesia. L-Arg pretreatment increased the analgesic effect of morphine. Repeated pretreatment (three times, at 24-h intervals) with L-NNA diminished both acute and chronic tolerance to morphine, whereas both the acute and the chronic morphine-induced tolerance increased after the repeated (three times, at 24-h intervals) administration of L-Arg. Neither L-NNA nor L-Arg affected the signs of morphine dependence, as assessed by naloxone (1 mg/kg, s.c.)-precipitated withdrawal. Our data suggest that increased NO synthesis potentiates morphine analgesia and enhances the development of morphine tolerance in mice.     

Effects of caerulein and CCK antagonists on tolerance induced to morphine antinociception in mice

Different groups of mice received one daily dose (50 mg/kg) of morphine subcutaneously (SC) for 3, 4 or 5 days to develop tolerance to the opioid. The antinociceptive response of morphine (9 mg/kg) was tested in the hot-plate test 24 h after the last dose of the drug. Tolerance to morphine was obtained in all groups. The group of mice that received morphine for 4 days was employed for the rest of the experiments. Pretreatment of animals with a single dose of caerulein (0.025, 0.05, and 0.1 mg/kg, SC) 30 min prior to receiving morphine (50 mg/kg; during the development of tolerance to the opioid) on day 1, 2, 3, 4 or 5 of morphine administration potentiate antinociception induced by morphine (test dose of 9 mg/kg). The dose of 0.05 mg/kg of caerulein, used 30 min before morphine administration on day 3, was also used to evaluate the effects of antagonists on caerulein-induced decrease in tolerance. The selective cholecystokinin (CCK) receptor antagonists, MK-329 [1-methyl-3-(2 indoloyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one; 0.25 and 0.5 mg/kg] or L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H- 1,4-benzodiazepin-3-yl)-N-(3-methyl-phenyl)urea: 0.25 and 0.5 mg/kg] decreased potentiation of morphine response induced by caerulein. MK-329 or L-365,260, when were injected 35 min before morphine injection during the development of tolerance and on day 3, decreased the tolerance to morphine. A single administration of MK-329 or L-365,260 (in the absence of caerulein) 35 min and 48 h before the test dose of morphine (9 mg/kg) potentiated the antinociception of morphine in nontolerant animals. In conclusion, CCK mechanism(s) may interact with morphine tolerance.     

Does dizocilpine (MK-801) inhibit the development of morphine-induced behavioural sensitization in rats?

Intermittent morphine pretreatment (10 mg/kg/day for 14 days) induced long-lasting (one month post-treatment) sensitization to the locomotor effects of morphine and amphetamine in rats. Co-administration of the non-competitive NMDA-receptor antagonist dizocilpine (MK-801) (0.1 mg/kg) with morphine did not prevent the development of long-term behavioural sensitization. However, this dose of MK-801 did cause long-term sensitization to its own locomotor effects. Co-administration of 0.25 mg/kg MK-801 with morphine caused death in 60% of the animals. In the animals that survived MK-801 plus morphine pretreatment, neither short-term (3 days) nor long-term morphine-induced sensitization was observed. MK-801 alone (0.25 mg/kg/day for 14 days) induced short-term cross-sensitization to morphine. Thus, the development of long-term morphine-induced locomotor sensitization could only be prevented by a dose of MK-801 that yields a lethal combination with morphine. In addition, MK-801 induced sensitization to its own locomotor effects and cross-sensitization to morphine. These findings seriously question whether MK-801 can be used to study the development of morphine-induced behavioural sensitization.     

Safety of Brucella abortus strain RB51 in Bison

We compared the efficacy of two clinically available drugs with N-methyl-D-aspartate receptor antagonist properties, dextromethorphan and ketamine, in potentiating morphine-induced antinociception. Ketamine alone at 0.3-3 mg/kg had no effect on the hot plate test and at 10 mg/kg caused sedation/motor deficits. The antinociceptive effect of 5 mg/kg morphine was slightly enhanced by 1 mg/kg, but not 0.3 or 3 mg/kg, ketamine. Dextromethorphan alone at 45 mg/kg had no effect, but at 60 mg/kg caused sedation/motor deficit. At 15-45 mg/kg, dextromethorphan significantly and dose-dependently increased the magnitude and duration of morphine-induced antinociception. Dextromethorphan also potentiated morphine at doses that, by themselves, did not cause antinociception (1-2 mg/kg). Implications: Dextromethorphan was more effective than ketamine in potentiating morphine-induced antinociception. Dextromethorphan may thus be the drug of choice for testing the interactions between N-methyl-D-aspartate antagonists and morphine clinically.     

Effects of systemic, intracerebral, or intrathecal administration on an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats.

A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)