ACETYLCHOLINE IN THE BRAIN OF MORPHINE TOLERANT AND NON-TOLERANT RATS.
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Acetylcholine↗
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Bovine adrenal medulla 22 reverses antinociceptive morphine tolerance in the rat.
Acute intrathecal (i.t.) bovine adrenal medulla 22 (BAM22, 10 nmol), an endogenous opioid peptide, induced equipotent thermal antinociception in naïve and morphine-tolerant rats while chronic BAM22 resulted in hyperalgesia and decrease in the effectiveness of antinociception. In rats made tolerant to morphine, prior administration of BAM22 (10 nmol, i.t.) significantly resumed antinociceptive response of morphine. The present study demonstrated that BAM22 was able to modulate maintenance of morphine tolerance.
Algorithms↗
Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions.
Rats were housed on a cabinet designed to control their access to water or morphine solutions. They were trained to drink all of their fluid as morphine solutions or tap water during 5-minute access periods scheduled at 2 A.M., 8 A.M., 2 P.M. and 8 P.M. On this schedule, the morphine drinking rats consumed an average of 29, 27, 21 and 23% of their total daily fluid during the four respective access periods. The rats that had access to the 0.05% morphine solution drank an average of 53 mg/kg/day of morphine. Separate groups of rats were tested for morphine tolerance and dependence at 4-day intervals. Tolerance to the analgesic effect of challenge doses of morphine (3, 6 and 9 mg/kg) was first detected after 10 days of morphine drinking and reached a plateau after 18 days. Withdrawal scores for rats injected with 0.3 or 3 mg/kg of naloxone reached a plateau between 14 and 18 days of morphine drinking, whereas the scores of rats given 0.03 mg/kg were still increasing after 26 days of drinking. Plasma levels of morphine ranged between 167 and 300 ng/ml in blood samples collected 1 hour after each access period on the 18th day of morphine drinking. Six hours after the 8 A.M. access period, the levels of morphine in the plasma had decreased to 50% of the levels detected at 1 hour after the access period. Ninety percent of the rats accepted the morphine solutions and drank regularly for the 26 days the solutions were offered. They remained healthy throughout this period and, except for the fact that they gained 11% less body weight over the 26 days, they were visibly indistinguishable from the water drinking control rats.
Animals↗
The dopamine D3/2 agonist 7-OH-DPAT attenuates the development of morphine tolerance but not physical dependence in rats.
RATIONALE: The dopamine (DA) D3/2 agonist 7-OH-DPAT attenuates the acute antinociceptive, discriminative stimulus, locomotor activating, and reinforcing effects of mu agonists (for example, morphine). OBJECTIVES: To examine the ability of 7-OH-DPAT to modulate the development of morphine tolerance and physical dependence in the rat. METHODS: Morphine antinociception was assessed using a warm water tail-withdrawal procedure before and following chronic treatment with morphine (15 mg/kg)/7-OH-DPAT (0.3-3.0 mg/kg). Physical dependence was assessed following naloxone-precipitated (1.0 mg/kg) withdrawal in rats treated chronically with morphine (15 and 7.5 mg/kg)/7-OH-DPAT (1.0-10 mg/kg). RESULTS: 7-OH-DPAT attenuated the antinociceptive effects of morphine in both morphine naive and tolerant rats. Additionally, morphine tolerance was attenuated by the coadministration of 7-OH-DPAT in a dose- and time-dependent manner. The magnitude of the attenuation obtained when morphine and 7-OH-DPAT were administered at the same time was similar to that obtained when administration of these drugs was separated by 6 h, indicating that 7-OH-DPAT did not alter morphine pharmacokinetics. In rats rendered tolerant to morphine, the subsequent coadministration of morphine/7-OH-DPAT failed to reverse morphine tolerance, but did attenuate its further development. The level of physical dependence (number and frequency of withdrawal signs) was greater in rats treated with 15 than 7.5 mg/kg morphine. Under both treatment conditions, physical dependence was not altered by 7-OH-DPAT. In morphine-dependent (15 mg/kg) rats, 7-OH-DPAT (3.0 and 10 mg/kg) failed to precipitate withdrawal. CONCLUSION: The D3/2 agonist 7-OH-DPAT can attenuate the antinociceptive effects of morphine in both acute and chronic preparations as well as the development of morphine tolerance. 7-OH-DPAT does not, however, alter morphine physical dependence.
Animals↗
Modulation of acute morphine tolerance by corticotropin-releasing factor and dynorphin A in the mouse spinal cord.
Previously, we have demonstrated that intrathecally (i.t.) administered corticotropin-releasing factor (CRF) in mice produces stimulus-specific antinociception and modulation of morphine-induced antinociception by mechanisms involving spinal kappa opioid receptors. Recently, we also have found that CRF releases immunoreactive dynorphin A, a putative endogenous kappa opioid receptor agonist, from superfused mice spinal cords in vitro. Dynorphin A administered intracerebroventricularlly (i.c.v.) to mice has been shown to modulate the expression of morphine tolerance. In the present study, the possible modulatory effects of i.t. administered CRF as well as dynorphin A on morphine tolerance were studied in an acute tolerance model. Subcutaneous administration of 100 mg/kg of morphine sulfate (MS) to mice caused an acute tolerance to morphine-induced antinociception. The antinociceptive ED50 of MS was increased from 4.4 mg/kg (naive mice) to 17.9 mg/kg (4 hours after the injection of 100 mg/kg MS). To study the modulatory effects of spinally administered CRF and dynorphin A on the expression of morphine tolerance, CRF and dynorphin A were injected i.t. at 15 min and 5 min, respectively, before testing the tolerant mice by the tail-flick assay. The antinociceptive ED50 of MS in tolerant mice was decreased to 8.8 mg/kg and 7.1 mg/kg, respectively, after i.t. administration of CRF (0.1 nmol) and dynorphin A (0.2 nmol). In contrast, 0.5 nmol of alpha-helical CRF (9-41), a CRF antagonist and 0.4 nmol of norbinaltorphimine, a highly selective kappa opioid receptor antagonist, when administered i.t. at 15 min before the tail-flick test in tolerant mice, increased the antinociceptive ED50 of MS to 56.6 mg/kg and 88.8 mg/kg, respectively. These data confirmed the modulatory effect of dynorphin A on morphine tolerance and suggested that CRF, which releases dynorphin A in several central nervous system regions, also plays a modulatory role in the expression of morphine tolerance.
Animals↗
Effects of clonidine on pituitary-adrenocortical axis in morphine-tolerant rats and after naloxone-induced withdrawal.
The effects of systemically administered clonidine on pituitary-adrenocortical axis in morphine-tolerant rats and after naloxone-induced withdrawal were examined. In naive animals, clonidine (0.5 and 1 mg/kg s.c.) significantly increased plasma beta-endorphin-like immunoreactivity (beta-END-LI) and cortisol levels. This effect was significantly reduced in morphine-tolerant animals. Naloxone treatment induced an increase of plasma beta-END-LI and cortisol levels in morphine-tolerant animals. The increase in cortisol level after withdrawal was significantly reduced by clonidine. These results are consistent with an interaction between alpha 2-adrenoceptors and opioid systems in the control of pituitary-adrenocortical axis during morphine tolerance and withdrawal.
Animals↗
Decreased response to GABA-B agonists in longitudinal smooth muscle-myenteric plexus preparations from morphine-tolerant guinea-pigs.
1) Responsiveness of guinea-pig ileal longitudinal smooth muscle-myenteric plexus preparations to drugs activating GABA-B receptors was studied in morphine-tolerant animals. For this purpose morphine pellets (75 mg each) were implanted subcutaneously in guinea-pigs and experiments were performed three days later in electrically-stimulated ileal strips. 2) Activation of GABA-B receptors with GABA (10(-6) -10(-3) M) or (-)-baclofen (10(-6)-10(-3) M) caused a dose-related inhibition of twitch response that was about 80% lower in preparations from morphine-tolerant animals than in controls. This was found both in preparations maintained in the presence of morphine (10(-6) M) and in morphine-free Krebs. The effect was evident also in ileal preparations from morphine-tolerant animals in which a withdrawal syndrome was induced by the administration of naloxone before sacrifice. 3) The phenomenon was specific since the dose-response curve of the adenosine-inhibitory effect was comparable in preparations from tolerant animals and controls. 4) The hyporesponsiveness to GABA-B receptor activation began 12 h after pellet implantation and was maximal on the third day. 5) It is concluded that during tolerance to and withdrawal from morphine there is a hyporesponsiveness of GABA-B receptors in "in vitro" guinea-pig ileal longitudinal muscle-myenteric plexus preparations.
Animals↗
Analgesia produced by low doses of the opiate antagonist naloxone in arthritic rats is reduced in morphine-tolerant animals.
In a model of experimental chronic pain (adjuvant-induced arthritic rats), low doses of the opiate antagonist naloxone produced a profound analgesia. Maximum analgesia was seen with 3 micrograms/kg (i.v.). In contrast, hyperalgesia was obtained with much higher doses (1-3 mg/kg, i.v.). The hyperalgesic effects were not affected in arthritic animals rendered tolerant to morphine, but the paradoxical analgesic effects were significantly reduced. This decrease suggests that naloxone analgesia involves interaction with opiate receptors and that the operation of endorphinergic systems differs in normal animals and animals which experience persistent pain.
Animals↗
Additive effect of dextromethorphan on the inhibitory effect of anti-NT4 on morphine tolerance.
It has been proposed that opioid tolerance is a model of neuronal plasticity similar to learning and memory. Recent evidence suggests that neurotrophins may be involved in synaptic development and plasticity. Observations indicate that neurotrophin 4 (NT4) is required for the synaptic plasticity mediating both tolerance and memory. Also there are lines of evidence to indicate that NMDA receptors are involved in the neural plasticity underlying the development of opiate tolerance. Neurotrophins affect central transmission postsynaptically by enhancing NMDA receptor responsiveness. So we used the clinically available NMDA receptor antagonist, dextromethorphan, and the neurotrophin 4 antibody, anti-NT4, concomitantly and alone to investigate their effects on morphine tolerance. Tolerance was induced by injecting morphine (7 and 10 mg/kg i.p.) once per day for 4 days. Anti-NT4 (1 microg/rat i.c.v.) was administered 15 min before morphine. Results showed that chronic concomitant treatment of anti-NT4 with morphine in both doses inhibited the development of morphine tolerance. Also acute treatment of anti-NT4 significantly reversed the tolerance that was induced by morphine 7 mg/kg but failed to reverse the tolerance of morphine 10 mg/kg. Dextromethorphan in both doses (10 or 30 mg/kg) has an additive effect on the inhibitory effect of anti-NT4 on the reversal of morphine tolerance (7 mg/kg). These findings provide additional support for the hypothesis that NMDA receptor and NT4 may be involved in neural plasticity underlying opiate tolerance.
Analgesics, Opioid↗
Absence of environment-specificity in morphine tolerance acquired in non-distinctive environments: habituation or stimulus overshadowing?
The experiments reported here investigated the mechanisms of drug tolerance acquisition in environments differing in distinctiveness. Specifically, they examined the hypothesis that tolerance acquired in non-distinctive environments might involve habituation while tolerance acquired in distinctive environments involves a classical conditioning or associative learning mechanism. In Experiment 1, rats pre-exposed to injection-ritual cues (placebo injections) prior to acquisition of tolerance to morphine analgesia in distinctive or non-distinctive environments showed a typically attenuated tolerance response on an environment-change test. The magnitude of the attenuation was not affected by the distinctiveness of the acquisition environment. In Experiment 2, rats acquiring tolerance in distinctive or non-distinctive environments, but without prior injection-ritual pre-exposure, did not demonstrate an attenuation of tolerance on an environment-change test. Tolerance acquired in either environment was unaffected by a subsequent rest period in the colony room, but was attenuated by a subsequent period of daily placebo injections in the colony room. It is argued that failure to observe environment-specific tolerance, as in Experiment 2 and in previous reports in the literature, may reflect overshadowing of environmental stimuli by injection-ritual stimuli, and are not indicative of a fundamental difference between the mechanisms of tolerance acquisition in environments varying in distinctiveness.
Analysis of Variance↗
Morphine tolerance offers protection from radiogenic performance deficits.
When rats are exposed to a sufficiently large dose of ionizing radiation they exhibit lethargy, hypokinesia, and deficits in performance. These and other behavioral changes parallel those often observed in this species after a large dose of morphine. Since the release of endogenous opiates has been implicated in some stress reactions, we sought to determine if they might play a part in radiogenic behavioral deficits. Rats were trained to criterion on a signaled avoidance task. Some subjects were then implanted with a pellet containing 75 mg of morphine. Other animals received placebo implants. Over a number of days, morphine tolerance was evaluated by measurement of body temperature changes. Prior to 2500 rad 60Co exposure or sham irradiation, morphine (or placebo) pellets were removed. Twenty-four hours later rats were retested to assess their performance on the avoidance task. Morphine-tolerant subjects performed significantly better than the irradiated placebo-implanted group and no differently than morphine-tolerant/sham-irradiated animals. Morphine tolerance seems to provide a degree of behavioral radiation resistance. These data are consistent with the hypothesis that endogenous opiate hyperexcretion may play some part in the behavioral deficits often observed after irradiation.
Animals↗
ANALGESIC ACTION AND BRAIN AND PLASMA LEVELS OF MORPHINE AND CODEINE IN MORPHINE TOLERANT, CODEINE TOLERANT AND NON-TOLERANT RATS.
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Analgesics↗
Development of morphine tolerance under tonic control of brain oxytocin.
Acute morphine tolerance was induced in mice by subcutaneous (s.c.) injection of a high dose (30 or 100 mg/kg) of morphine. The degree of tolerance was estimated 5 h later. Intracerebroventricular (i.c.v.) injection of graded doses of oxytocin (OXT) dose-dependently attenuated the development of tolerance. i.c.v. injection of a specific anti-OXT serum, on the other hand, facilitated the development of tolerance. Neither OXT nor anti-OXT serum had any effect on the pain sensitivity in morphine-naive mice; nor did these treatments modify the antinociceptive action of a single morphine treatment. It is concluded that the endogenous OXT of the mouse brain is normally involved in the adaptive response of the organism, leading to the development of morphine tolerance.
Adaptation, Physiological↗
Determination of the role of conventional, novel and atypical PKC isoforms in the expression of morphine tolerance in mice.
This study comprehensively determines the role of all the major PKC isoforms in the expression morphine tolerance. Pseudosubstrate and receptors for activated C-kinase (RACK) peptides inhibit only a single PKC isoform, while previously tested chemical PKC inhibitors simultaneously inhibit multiple isoforms making it impossible to determine which PKC isoform mediates morphine tolerance. Tolerance can result in a diminished effect during continued exposure to the same amount of substance. In rodents, morphine pellets provide sustained exposures to morphine leading to the development of tolerance by 72 h. We hypothesized that administration of the PKC isoform inhibitors i.c.v. would reverse tolerance and reinstate antinociception in the tail immersion and hot plate tests from the morphine released solely from the pellet. Inhibitors to PKC alpha, gamma and epsilon (100-625 pmol) dose-dependently reinstated antinociception in both tests. The PKC beta(I), beta(II), delta, theta, epsilon, eta and xi inhibitors were inactive (up to 2500 pmol). In other mice, the degree of morphine tolerance was determined by calculating ED50 and potency-ratio values following s.c. morphine administration. Morphine s.c. was 5.6-fold less potent in morphine-pelleted vs. placebo-pelleted mice. Co-administration of s.c. morphine with the inhibitors i.c.v. to either PKC alpha (625 pmol), gamma (100 pmol) or epsilon (400 pmol) completely reversed the tolerance so that s.c. morphine was equally potent in both placebo- and morphine-pelleted mice. The PKC beta(I), beta(II), delta, theta, epsilon, eta and xi inhibitors were inactive. Thus, PKC alpha, gamma and epsilon appear to contribute to the expression of morphine tolerance in mice.
Analgesics, Opioid↗
Analog of neuropeptide FF attenuates morphine tolerance.
Previous studies suggest that neuropeptide FF (NPFF) plays a role in opiate dependence and subsequent abstinence syndrome. Endogenous NPFF also appears to play a role in opiate tolerance since third ventricle injection of IgG from NPFF antiserum selectively restores morphine sensitivity in morphine-tolerant rats. The NPFF analog, desamino YFLFQPQRamide (daY8Ra) has previously antagonized behavioral effects of NPFF and has attenuated morphine dependence. The present study assessed whether daY8Ra could similarly attenuate morphine tolerance. Third ventricle (i.c.v.) injection of daY8Ra restored the analgesic response to i.c.v. morphine in morphine-tolerant rats (radiant heat tail flick test). Saline injection failed to produce this effect. In opiate-naive rats, however, the same treatment with daY8Ra did not affect the analgesic response to i.c.v. morphine. Thus, daY8Ra appears to selectively restore morphine sensitivity in opiate-tolerant animals. These results further support the hypothesis that endogenous NPFF contributes to opiate tolerance.
Amino Acid Sequence↗
The involvement of glial cells in the development of morphine tolerance.
Glial response to chronic morphine treatment was examined by immunohistochemistry of glial fibrillary acidic protein (GFAP), a specific marker for astroglial cells. Systemic administration of morphine (50 mg/kg, i.p.) once daily for 9 consecutive days led to significant increase in GFAP immunostaining density in the spinal cord, posterior cingulate cortex and hippocampus but not in the thalamus. This increase was attributed primarily to hypertrophy of astroglial cells rather than their proliferation or migration. When chronic morphine (20 microg/2 microl, i.t.) was delivered in combination with fluorocitrate (1 nmol/1 microl, i.t.), a specific and reversible inhibitor of glial cells, spinal tolerance to morphine analgesia was partly but significantly attenuated as measured by behavioural test and the increase in spinal GFAP immunostaining was also greatly blocked. The present investigation provides the first evidence for the role of glial cells in the development of morphine tolerance in vivo.
Analgesics, Opioid↗
The competitive NMDA receptor antagonist LY235959 modulates the progression of morphine tolerance in rats.
A rat warm-water tail-withdrawal procedure was used to examine the effects of chronic administration of the competitive NMDA receptor antagonist LY235959 in morphine tolerant rats. Morphine dose-dependently increased tail-withdrawal latencies from 55 degree C water. When morphine (10 mg/kg) was administered twice-daily for 7 days, the morphine dose-effect curves shifted 0.3-0.5 log unit to the right. When morphine was administered for an additional 7 days, the morphine dose-effect curve shifted 0.4 log unit further to the right. Co-administration of LY235959 (1, 3, 10 mg/kg) along with morphine prevented the development of tolerance observed during the second week of chronic morphine administration. Although the highest dose of LY235959 (10 mg/kg) partially reversed tolerance in five of seven rats, tolerance was not reversed by lower doses of LY235959. These data suggest that NMDA receptor antagonists may effectively prevent the progressive development of morphine tolerance at doses that are not sufficient to reverse pre-established morphine tolerance.
Analgesics, Opioid↗
Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance.
The neuropeptide orphanin FQ/nociceptin (OFQ/N) has been shown to counteract several effects of endogenous and exogenous opioids, and it has been proposed as an opioid-modulating agent involved in the development of morphine tolerance and dependence. However, conflicting results have been obtained from animal models using different protocols to induce morphine tolerance. Here, we report that both genetic and pharmacological blockade of OFQ/N signaling can effectively prevent development of morphine tolerance. OFQ/N knockout mice injected daily with low doses of morphine (10 mg/kg) fail to develop tolerance even after 3 weeks of treatment, whereas their wild-type litter mates show profound tolerance starting after 10 days. Likewise, coadministration of morphine together with the synthetic N/OFQ peptide antagonist, J-113397 (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), is able to block tolerance development in normal mice. These data indicate that release of endogenous OFQ/N after morphine administration might produce a gradual decline of analgesic potency, i.e., tolerance. Interestingly, tolerant and nontolerant groups of mice receiving repeated daily low morphine doses did not differ in their withdrawal behavior after naloxone injection. In contrast, mice receiving escalating doses of morphine developed analgesic tolerance independent of their OFQ/N genotype, whereas withdrawal symptoms were attenuated in OFQ/N-deficient animals. These results indicate that the endogenous OFQ/N system is differentially involved in morphine tolerance development and establishment of opiate dependence, depending on the specific morphine dosage regimen. Furthermore, it suggests that OFQ/N antagonists could provide a novel therapeutic strategy to attenuate morphine tolerance development.
Animals↗