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PubMed1994

Effect of morphine tolerance and abstinence on the binding of [3H]naltrexone to discrete brain regions and spinal cord of the rat.

1. The effect of morphine tolerance and abstinence on the binding of [3H]naltrexone to discrete brain regions and spinal cord of the rat was determined. 2. Male Sprague-Dawley rats were implanted s.c. under light ether anesthesia with six morphine pellets for a 7-day period. Each pellet contained 75 mg of morphine base. Rats implanted with six placebo pellets each served as controls. 3. This procedure resulted in the development of tolerance to morphine as evidenced by decreased analgesic response to various doses of morphine. 4. The binding characteristics (Bmax or Kd values) of [3H]naltrexone, an opiate receptor antagonist, were determined in various tissues of morphine tolerant and abstinent rats. In the tolerant rats, the pellets were left in place at the time of sacrificing, whereas in the abstinent rats, the pellets were removed 18 hr prior to sacrificing. 5. The binding of [3H]naltrexone to opiate receptors on membranes prepared from brain regions (hypothalamus, hippocampus, cortex, pons and medulla, midbrain, corpus striatum and amygdala) and spinal cord of rats from various treatment groups was determined. 6. [3H]Naltrexone bound to tissue membranes at a single high affinity binding sites. The Bmax values of [3H]naltrexone to bind to opiate receptors on the membranes of amygdala and striatum were increased significantly in morphine tolerant rats when compared to the placebo controls, but the Kd values did not differ. 7. The Bmax and Kd values of [3H]naltrexone did not differ in any other brain region or spinal cord of morphine tolerant rats and their placebo controls. The binding constants of [3H]naltrexone were unaffected in morphine abstinent rats. 8. Previously we had shown that the binding of [3H]D-Ala2, MePhe4, Gly-ol5 enkephalin (DAMGO), a highly specific agonist for mu-opiate receptors was decreased in cortex, pons and medulla and spinal cord of morphine tolerant but not in the abstinent rats. In addition, delta and kappa receptors are unaffected in morphine tolerant and abstinent rats. 9. The results suggest that direction of change, as well as, the brain areas for mu-agonist and -antagonist opiate binding sites are affected differentially in morphine tolerant rats.

Analgesics↗
PubMed2003

Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111).

(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED(50) = 0.69 mg/kg, 95% confidence limit (CL) = 0.34-1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED(50) = 0.62 mg/kg i.v., 95% CL = 0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.

Animals↗
PubMed1984

Potentiation of narcotic-induced antinociception by tripelennamine in morphine-tolerant and drug-naive mice.

The ability of tripelennamine and chlorpheniramine to potentiate morphine- and pentazocine-induced antinociception in drug-naive and morphine-tolerant mice was tested utilizing the hot-plate method. Both tripelennamine and chlorpheniramine alone produced dose-dependent increases in hot plate latency which were naloxone reversible. Cross-tolerance developed between tripelennamine and morphine, whereas no cross-tolerance developed between chlorpheniramine and morphine. Neither tripelennamine nor chlorpheniramine significantly potentiated morphine-induced antinociception in drug-naive mice. The effects of tripelennamine and morphine were additive. Tripelennamine but not chlorpheniramine, however, significantly potentiated antinociception produced by low but not high doses of pentazocine in drug-naive mice. Furthermore, in morphine-tolerant mice, tripelennamine, but not chlorpheniramine, potentiated both morphine- and pentazocine-induced antinociception. It is concluded that the abuse of various narcotic-tripelennamine combinations can be attributed, at least in part, to a specific property of tripelennamine to potentiate narcotic effects in the drug-naive and morphine-tolerant state.

Analgesia↗
PubMed2005

Systemic administration of propentofylline does not attenuate morphine tolerance in non-injured rodents.

Propentofylline is a phosphodiesterase inhibitor that has been shown to attenuate the onset of morphine tolerance when administered intrathecally to rats. The present studies examined whether systemic administration could be effective in attenuating morphine tolerance in non-injured rodents using a similar dosing paradigm. Propentofylline at 10, 30, or 50 mg/kg, administered intraperitoneally once daily for 5 days, was unable to attenuate morphine tolerance established by twice daily administration of 10 mg/kg morphine. These results suggest that direct delivery of propentofylline to the central nervous system (CNS) may be required in order to attenuate morphine tolerance.

Analgesia↗
PubMed2002

Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity.

Tolerance to the analgesic effects of an opioid occurs after its chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we examined the role of spinal glutamate transporters (GTs) in the development of both morphine tolerance and associated thermal hyperalgesia. Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation of GTs (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn. This GT downregulation was mediated through opioid receptors because naloxone blocked such GT changes. Morphine-induced GT downregulation reduced the ability to maintain in vivo glutamate homeostasis at the spinal level, because the hyperalgesic response to exogenous glutamate was enhanced, including an increased magnitude and a prolonged time course, in morphine-treated rats with reduced spinal GTs. Moreover, the downregulation of spinal GTs exhibited a temporal correlation with the development of morphine tolerance and thermal hyperalgesia. Consistently, the GT inhibitor l-trans-pyrrolidine-2-4-dicarboxylate (PDC) potentiated, whereas the positive GT regulator riluzole reduced, the development of both morphine tolerance and thermal hyperalgesia. The effects from regulating spinal GT activity by PDC were at least in part mediated through activation of the NMDA receptor (NMDAR), because the noncompetitive NMDAR antagonist MK-801 blocked both morphine tolerance and thermal hyperalgesia that were potentiated by PDC. These results indicate that spinal GTs may contribute to the neural mechanisms of morphine tolerance and associated abnormal pain sensitivity by means of regulating regional glutamate homeostasis.

Amino Acid Transport System X-AG↗
PubMed1983

Arginine vasopressin enhances retention of morphine tolerance.

The hot plate method was used to assess tolerance in rats following daily injections of morphine. Following analgesia assessment, or a time equated rest period, rats were injected with either saline or a pituitary peptide. Arginine vasopressin, but not ACTH 4-10, prolonged the retention of morphine tolerance when assessed five weeks after the last injection. Neither the rate nor the degree of tolerance development were influenced by either peptide. These hormones had no effect on retention of tolerance development were influenced by either peptide. These hormones had no effect on retention of tolerance in rats not assessed for analgesia during the period of tolerance development. The effects of pituitary peptides on morphine tolerance are analogous to the effects they have on learning and memory processes, suggesting that similar adaptational processes are occurring in both phenomena.

Adrenocorticotropic Hormone↗
PubMed1989

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation.

The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

mu-Opioid receptor down-regulation and cAMP-dependent protein kinase phosphorylation in a mouse model of chronic morphine tolerance.

Results of radioligand binding and transfected receptor studies indicate that mu-receptor down-regulation and phosphorylation may be critical to the expression of morphine tolerance. In this study, an animal model of morphine tolerance was used to correlate antinociception with changes in receptor number and phosphorylation state. mu-Opioid receptor protein was quantitated by Western immunoassay of brainstem tissue from morphine-treated mice. Degree of receptor phosphorylation was assessed using immunoprecipitation (IP) of the receptor followed by back-phosphorylation. Acutely administered morphine produced no changes in mu-receptor quantity. Chronic morphine administration resulted in a 50% reduction in receptor protein quantity over placebo-treated samples. Back-phosphorylation experiments showed a drop in cAMP-dependent protein kinase A (PKA)-induced receptor phosphorylation shortly after acute morphine administration, followed by a naloxone-reversible increase in phosphorylation of the receptor that correlated with the onset of antinociception. Chronic morphine administration resulted in a decrease in PKA-induced phosphorylation of the mu-receptor. Since it has been shown that PKA activity is enhanced in the brains of morphine-tolerant mice, this decrease in mu-receptor phosphorylation suggests that the mu-receptor may be structurally or conformationally altered in the morphine-tolerant state.

Animals↗
PubMed2003

Ontogeny of NMDA receptor-mediated morphine tolerance in the postnatal rat.

N-methyl-D-aspartate (NMDA) receptor antagonists are effective in inhibiting the development of morphine tolerance in adult rats. But NMDA receptors undergo dramatic change during the first few weeks of the postnatal life in the rat, and it is unknown whether NMDA receptor antagonists can inhibit the acquisition of opiate tolerance in the developing organism. Here, we investigated the effects of two NMDA receptor antagonists MK-801 and dextromethorphan on the development of morphine tolerance in 7-, 14-, and 21-day-old rats. NMDA receptor antagonists are not effective in attenuating morphine tolerance in the neonatal rat whereas they were partially effected in the 14-day-old and fully effective in rats as old or older than 21 days of age. These data suggest that there exists a transition age, around the second postnatal week in the rat, for the NMDA receptor to play a role in the development of morphine tolerance.

Animals↗
PubMed1997

[Experimental study of selective muscarinic receptor antagonists on attenuation of morphine tolerance and dependence in rats].

OBJECTIVE: To characterize the role of muscarinic receptor subtype in the process of the morphine tolerance and dependence. METHODS: The morphine (Antinociception) tolerance was assessed by using hot-plate latency, and morphine dependence was characterized by naloxone-precipitated withdrawal. Intraperitoneal (i.p.) or intrathecal (i.t.) injection of muscarinic M1 selective antagonist pirenzepine or M2 selective antagonist methoctramine was carried out. RESULTS: Methoctramine (i.p.) for 6 days restored the sensitivity to morphine in male Sprague Dawley rats that are tolerant as a result of 6 days of b.i.d. morphine injection, in contrast, saline and pirenzepine (i.p.) did not increase the mean HP latency of morphine tolerant rats. Both methoctramine and pirenzepine in doses did not alter the baseline HP latency. Concurrent treatment with pirenzepine (i.t.) significantly attenuated the development of morphine tolerance produced by twice daily injection of morphine in a dose-dependent manner, however, methoctramine (i.t.) also decreased without dose-relation. In addition, the withdrawal symptoms precipitated by naloxone in morphine dependent rats were blocked by methoctramine (i.p.) or pirenzepine (i.t.) at single dose injection in a dose-dependent manner. Methoctramine (i.t.) at 200 micrograms/kg could partially inhibit the withdrawal symptoms. CONCLUSIONS: The data suggested that the muscarinic receptor subtype predominating M2 receptor at the peripheral and M11 in the spinal cord mediate the process of morphine tolerance and dependence in rat.

Animals↗
PubMedDate not supplied

The influence of amphetamine and nomifensine on the development of morphine tolerance in the test of hypermotility in mice and catalepsy in rats.

The influence of drugs, which alter the brain catecholaminergic functions, on the development of morphine tolerance was studied. The experiments were carried out on mice in locomotor activity test, and on rats in catalepsy test. Tolerance to morphine was induced by subcutaneous implantation of morphine-base (37.5 mg) pellets. Amphetamine insignificantly diminished the development of tolerance to cataleptogenic effects of morphine in rats but markedly inhibited the development of tolerance to morphine-induced hyperactivity in mice. The latter action of amphetamine was blocked by pimozide. Administration of nomifensine induced the inhibition of the development of morphine tolerance in both tests. Pimozide also abolished this antagonistic action of nomifensine in locomotor activity test in mice. The obtained results have shown that intensification of dopaminergic neurotransmission induced the diminution of the development of tolerance to morphine.

Amphetamine↗
PubMed2003

Inhibition of neurokinin-1-substance P receptor and prostanoid activity prevents and reverses the development of morphine tolerance in vivo and the morphine-induced increase in CGRP expression in cultured dorsal root ganglion neurons.

Chronic treatment with opioid drugs such as morphine leads to the development of tolerance, which manifests as a loss of drug potency. The mechanisms underlying this phenomenon are poorly understood, but recent evidence suggests that increased activity of nociceptive sensory transmitters [calcitonin gene-related peptide (CGRP) and substance P] and other signalling messengers (prostaglandins) contribute to its development. Chronic intrathecal morphine administration to rats for 7 days produced analgesic tolerance. Co-administration of SR140333, a selective substance P receptor (neurokinin-1) antagonist, or nimesulide, a cyclooxygenase-2-selective inhibitor, augmented the acute effects of morphine, prevented morphine tolerance and reversed established tolerance. In cultured adult dorsal root ganglion neurons, exposure to morphine for 5 days increased the number of neurons expressing CGRP immunoreactivity. Co-exposure with the peptide CGRP receptor antagonist CGRP8-37, SR140333 or nimesulide prevented the morphine-induced increase in the expression of CGRP immunoreactivity. Additionally, BIBN4096BS, a nonpeptide CGRP receptor antagonist, stereoselectively produced similar effects. In summary, this investigation demonstrates that activity of CGRP and substance P contributes to both the induction and expression of opioid analgesic tolerance. Additionally, it highlights the involvement of prostaglandins generated by spinal cyclooxygenase-2 activity in the genesis of opioid tolerance. The neuropeptide and prostanoid activity contributing to tolerance is expressed at the level of the primary afferents terminating in the spinal cord. The combination of opioids with agents that block this activity may represent a useful strategy for the prevention as well as the reversal of clinical opioid tolerance.

Animals↗
PubMed2006

PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice.

Male Swiss Webster mice exhibited antinociception, hypothermia and Straub tail 3h following a 75mg morphine pellet implantation. These signs disappeared by 72h, and the morphine-pelleted mice were indistinguishable from placebo-pelleted ones, although brain morphine concentrations ranged from 200 to 400ng/gm. We previously demonstrated that chemical inhibitors of protein kinase C (PKC) and A (PKA) are able to reverse morphine tolerance in acutely morphine-challenged mice. However, it was not known whether the reversal of tolerance was due to the interaction of kinase inhibitors with the morphine released from the pellet, the acutely injected morphine to challenge tolerant mice, or both. The present study aimed at determining the interaction between the PKC and PKA inhibitors and the morphine released "solely" from the pellet to reinstate the morphine-induced behavioral and physiological effects, 72h after implantation of morphine pellets. Placebo or 75mg morphine pellets were surgically implanted, and testing was conducted 72h later. Our results showed that the intracerebroventricular (i.c.v.) administration of the PKC inhibitors, bisindolylmaleimide I and Gö-6976 as well as the PKA inhibitors, 4-cyano-3-methylisoquinoline and KT-5720, restored the morphine-induced behaviors of antinociception, Straub tail and hypothermia in morphine-pelleted mice to the same extent observed 3h following the pellet implantation. The tail withdrawal and the hot plate reaction time expressed as percent maximum possible effect (%MPE) was increased to 80-100 and 41-90%, respectively, in PKC and PKA inhibitor-treated morphine tolerant mice compared to 2-10% in non-treated mice. Similarly, a significant hypothermia (1.3-4.0 degrees C decrease in body temperature) was detected in PKC and PKA inhibitor-treated morphine tolerant mice compared to an euthermic state in non-treated morphine tolerant mice. Finally, the Straub tail score was increased to 1.1-1.6 in PKC and PKA inhibitor-treated tolerant mice, whereas it was totally absent in non-treated animals. It is noticeably that the kinase inhibitors used in the study had no effect in placebo-pelleted mice. Our results provide the first evidence on the ability of PKC and PKA inhibitors to reinstate the behavioral and physiological effects of morphine in non-challenged morphine-tolerant animals.

Analgesics, Opioid↗
PubMed1999

Inhibition of calcium/calmodulin-dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence.

Learning and memory have been suggested to be important in the development of opiate addiction. Based on the recent findings that calcium/calmodulin-dependent protein kinase II (CaMKII) is essential in learning and memory processes, and morphine treatment increases CaMKII activity in hippocampus, the present study was undertaken to examine whether inhibition of hippocampal CaMKII prevents morphine tolerance and dependence. Here, we report that inhibition of CaMKII by intrahippocampal dentate gyrus administration of the specific inhibitors KN-62 and KN-93 to rats significantly attenuated the tolerance to the analgesic effect of morphine and the abstinence syndrome precipitated by opiate antagonist naloxone. In contrast, both KN-04 and KN-92, the inactive structural analogs of KN-62 and KN-93, failed to attenuate morphine tolerance and dependence, indicating that the observed effects of KN-62 and KN-93 are mediated through inhibition of CaMKII. Furthermore, administration of CaMKII antisense oligonucleotide into rat hippocampal dentate gyrus, which decreased the expression of CaMKII specifically, also attenuated morphine tolerance and dependence, while the corresponding sense oligonucleotide of CaMKII did not exhibit such inhibitory effect. Moreover, the KN-62 treatment abolished the rewarding properties of morphine as measured by the conditioned place preference. These results suggest that hippocampal CaMKII is critically involved in the development of morphine tolerance and dependence, and inhibition of this kinase may have some therapeutic benefit in the treatment of opiate tolerance and dependence.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Alternation of galanin in nociceptive modulation in the central nervous system of rats during morphine tolerance: a behavioral and immunohistochemical study.

The present study was performed to investigate the alternation of galanin in nociceptive modulation and galanin-like immunoreactivity in the central nervous system of rats after morphine tolerance. The hindpaw withdrawal latencies to both thermal and mechanical stimulation increased significantly after intracerebroventricular injection of 3 nmol of galanin in opioid-naive rats. The antinociceptive effect induced by galanin was attenuated remarkably at the same dose in morphine-tolerant rats. Furthermore, an up-regulation of galanin-like immunoreactivity in the arcuate nucleus of hypothalamus of morphine-tolerant rat was observed by immunohistochemical methods, whereas no significant changes were detected in periaqueductal gray. The present study demonstrated that there are alternations in both galanin-induced antinociception and galanin-like immunoreactivity in the brain of rat after morphine tolerance. The results suggest an involvement of galanin in the central nervous system in morphine tolerance.

Analysis of Variance↗
PubMed2005

An opiate cocktail that reduces morphine tolerance and dependence.

Morphine is an exceptionally effective analgesic whose utility is compromised by the development of tolerance and dependence to the drug. Morphine analgesia and dependence are mediated by its activity at the mu opioid peptide (MOP) receptor [1]. The MOP receptor is activated not only by morphine, but also by other opiate drugs such as methadone and endogenous opioids such as endorphins. Morphine, however, is a unique opioid agonist ligand because it fails to induce endocytic trafficking of the MOP receptor [2], whereas the endogenous ligands and methadone do facilitate endocytosis [3]. Using the unique pharmacology of the MOP receptor and its proposed existence as an oligomeric structure [4], we designed a pharmacological cocktail that facilitates endocytosis of the MOP receptor in response to morphine. This cocktail consists of morphine and a small dose of methadone. Importantly, this cocktail, while retaining full analgesic potency, does not promote morphine dependence. We further demonstrate that dependence is reduced, at least in part, because endocytosis of the MOP receptor in response to morphine prevents the upregulation of N-methyl-D-aspartate (NMDA) receptors.

Analysis of Variance↗
PubMed1996

Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice.

1. The possible involvement of nitric oxide (NO) in the induction and expression of morphine tolerance and dependence was studied in mice. A two-day repeated injection regimen was used to induce morphine tolerance and dependence. Tolerance was assessed by the tail flick test and physical dependence by naloxone challenge, on the third day. 2. Two days pretreatment with L-arginine (20 mg kg-1, twice daily) or D-NG-nitro arginine methyl ester (D-NAME, 20 mg kg-1, twice daily) alone had no effect on subsequent morphine antinociception. L-NG-monomethyl arginine (L-NMMA, 10 mg kg-1, twice daily) for two days led to a slight increase (not statistically significant) in morphine antinociception; while L-NG-nitro arginine methyl ester (L-NAME, 10 mg kg-1, twice daily) for two days led to attenuation of morphine analgesia. None of the animals treated with these drugs alone showed signs characteristic of the opioid withdrawal syndrome upon naloxone challenge. 3. Induction phase L-arginine slowed the development of opioid tolerance and physical dependence, while L-NAME and L-NMMA led to a higher degree of tolerance but had no effect on the development of physical dependence. 4. L-Arginine and D-NAME had no effect on the expression of morphine tolerance and physical dependence. Expression phase L-NAME and L-NMMA, on the other hand, attenuated morphine tolerance and reduced the incidence of withdrawal signs. 5. NO may, therefore, play a role in both phases of morphine tolerance and dependence: elevation of NO levels during the induction phase delays the development of opioid tolerance/dependence, while inhibition of NO synthase accelerates the development of tolerance. Inhibition of NO attenuates the expression of both tolerance and physical dependence.

Animals↗