Tolerance to morphine in the rat: Associative and nonassociative effects.

Two experiments were conducted to examine the impact of dose level and interdose interval (IDI) on the development of tolerance to the analgesic effect of morphine. In Exp I, rats were administered a series of low- (5 mg/kg) or high- (30 mg/kg) dose injections of morphine either explicitly paired or unpaired with a distinctive context at a 48-hr IDI. The development of tolerance following this regimen was assessed by shifts in dose-response curves to the right when animals were tested on a tail-flick device in the distinctive context. Only animals that had received morphine paired with the distinctive context were tolerant to morphine; the magnitude of this associative tolerance was a positive function of the level of the conditioning dose. In Exp II, rats were exposed to a high dose of morphine (30 mg/kg) either paired or unpaired with a distinctive context at one of two IDIs (24 or 96 hr). Tolerance testing revealed that at the long IDI, only associative tolerance was evident, whereas at the short IDI, tolerance in the unpaired condition was more pronounced with a corresponding decline in the development of associative tolerance. The relevance of these findings for psychological theories of drug tolerance are discussed. Results are consistent with the predictions of an habituation model of drug tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interdose interval effects on the development of contextual tolerance to nicotine's analgesic effects in rats (Rattus norvegicus).

Learning models of associative and nonassociative drug tolerance predict that the development of contextual tolerance to drug effects is disrupted when the drug is delivered at short interdose intervals (IDIs). The authors examined the impact of 1 long IDI and 2 short IDIs in the development of contextual nicotine tolerance. Associative tolerance was investigated by giving rats (Rattus norvegicus) 10 subcutaneous injections of nicotine at either long (72-hr) IDIs or short (6-hr and 4.5-hr) IDIs. The delivery of nicotine was either explicitly paired or explicitly unpaired with a distinctive context. A 3rd group of rats was exposed to the experimental procedures but received only saline. Associative tolerance to nicotine's analgesic effects was defined as a shift to the right of the dose-response curve (DRC) of rats in the explicitly paired condition with respect to the DRC of rats in the explicitly unpaired condition. Analgesia was assessed with the tail-flick and hot-plate devices. In the tail-flick assessment, associative tolerance was evident in the 72-hr and the 6-hr IDI conditions only. In the hot-plate assessment, associative tolerance was present in the 72-hr IDI condition only. The findings suggest that contextual tolerance to nicotine's analgesic effects are positively related to IDI length and are more readily demonstrated with the tail-flick method than with the hot-plate method. Overall, the results supported the thesis that nicotine tolerances that develop to different IDIs are qualitatively different and may be mediated by different psychological and physiological mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphine enhancement of sucrose palatability: analysis by the taste reactivity test

The ability of morphine to modify sucrose palatability was assessed by the taste reactivity test. In Experiment 1, rats were injected with morphine (0.0, 0.5, 2.0, and 10.0 mg/kg, subcutaneously), 30 min before receiving a 10-min intraoral infusion of 2% or 20% sucrose solution. A dose of 2.0 mg/kg morphine enhanced ingestive reactions elicited by both concentrations of sucrose solution. In Experiment 2, the interval between morphine pretreatment and the taste reactivity test was manipulated. Rats given 2.0 mg/kg morphine 30 or 120 min before testing displayed enhanced ingestive reactions elicited by 20% sucrose solution during the first 5 min of a 10-min test. The results support the hypothesis that morphine enhances the hedonic assessment of sucrose solution.     

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.     

Ketamine attenuates and reverses morphine tolerance in rodents

BACKGROUND: The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance. METHOD: Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed. RESULTS: Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. CONCLUSIONS: Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.     

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.     

Amphetamine-induced withdrawal responding: effects of repeated drug administration

The first purpose of this research was to assess withdrawal haloperidol-appropriate lever responding 24 h after a single administration of 0.35, 0.75, and 1.00 mg/kg amphetamine. Rats were trained to discriminate among 0.35 mg/kg amphetamine (AM), distilled water (DW), and 0.033 mg/kg haloperidol (HA) in a three-lever drug discrimination task. An increase in HA-appropriate lever responding occurred following the 1.00 mg/kg dose of AM but not after either of the lower doses. The second purpose was to determine the effect of repeated administration of 0.75 mg/kg AM. Two groups of animals were given five administrations of drug, one at an interdose interval (IDI) of 24 h and the other at an IDI of 48 h. Control animals were given injections of DW. Increased HA-appropriate lever responding occurred in both of the AM-treated groups. The magnitude of this effect tended to be less in the 48-h IDI group. Thus, even though HA-lever responding was not evident 24 h after a single administration of 0.75 mg/kg AM, it was produced by repeated administration of this dose, even at 48-h intervals.     

Effects of ethanol on encoding, consolidation, and expression of extinction following contextual fear conditioning.

Studies of contextual fear conditioning have found that ethanol administered prior to a conditioning session impairs the conditioned freezing response during a test session the next day. The present experiments examined the effects of ethanol on extinction, the loss of conditioned responding that occurs as the animal learns that a previously conditioned context no longer signals shock. Ethanol (1.5 g/kg) administered prior to single (Experiment 1) or multiple (Experiment 2) extinction sessions impaired extinction. Ethanol administered prior to a test session disrupted the expression of freezing after extinction (Experiments 3-5). There was some evidence that ethanol served as an internal stimulus signaling the operation of conditioning or extinction contingencies (Experiments 4-5). In Experiment 6, postsession injections of 1.5 g/kg ethanol had no effect on extinction with brief (3 min) or long (24 min) exposures to the context, but injections of 3 g/kg after long exposures impaired extinction. Together, these results indicate that ethanol affects extinction by acting on multiple learning and performance processes, including attention, memory encoding, and memory expression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of partial reinforcement on tolerance to morphine-induced analgesia and weight loss in the rat.

Groups of 60 male Sprague-Dawley rats were presented a distinctive set of environmental cues on several occasions. For 1 group, morphine (40 mg/kg) was injected each time the cues were presented (morphine/continuous reinforcement). For a 2nd group, morphine was injected only following 1 of 4 cue presentations (morphine/partial reinforcement). Two additional groups were injected with only saline, one on the continuous reinforcement schedule and the other on the partial reinforcement schedule. Results demonstrate less tolerance to morphine in the partially reinforced morphine-injected Ss than in continuously reinforced morphine-injected Ss. Unlike other demonstrations of a tolerance-retarding effect of partial reinforcement, findings did not result from nonassociative factors related to differential novelty, stress, or practice. Clinical implications for the tolerance-retarding effect of partial reinforcement are discussed. (28 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Zaprinast, but not dipyridamole, reverses hemodynamic tolerance to nitroglycerin in vivo

Hemodynamic tolerance to nitroglycerin was developed in spontaneously hypertensive rats following 2-3 days of pretreatment with 100 mg/kg of nitroglycerin administered s.c. 3 times/day. Tolerance was evaluated both in vivo, by administering ascending bolus doses of nitroglycerin of 1-300 micrograms/kg i.v., and ex vivo in isolated, denuded aortic vascular rings by exposure to ascending concentrations of nitroglycerin of 0.0003-100 microM. Tolerance was observed as a significant blunting of the hypotensive and vasorelaxant effect of nitroglycerin. Co-incubation of tolerant aortic rings and pretreatment of tolerant SHR with 10 microM and 0.1-10 mg/kg zaprinast, respectively, resulted in full restoration of the vasorelaxant and hypotensive effect of nitroglycerin. Zaprinast partially reversed hemodynamic tolerance at 0.01 mg/kg. Conversely, dipyridamole (10 microM) reversed tolerance ex vivo, but was ineffective in reversing tolerance in vivo at pretreatment doses of 30 and 60 mg/kg. Following a 100-micrograms/kg i.v. challenge dose of nitroglycerin, aortic cyclic guanosine monophosphate (cGMP) levels were lower in nitroglycerin tolerant SHR when compared to non-tolerant SHR. Pretreatment of tolerant SHR with 10 mg/kg zaprinast restored the increase in cGMP levels to nitroglycerin to that seen in non-tolerant SHR. Conversely, dipyridamole (30 mg/kg) pretreatment was not effective in restoring cGMP levels. These data therefore suggest that reversal of hemodynamic tolerance in vivo is related to restoration of changes in vascular cGMP levels. Zaprinast, a selective cGMP phosphodiesterase inhibitor, effectively reverses tolerance and dipyridamole, a rather non-selective inhibitor, does not.     

Pavlovian conditioning and addictive behavior: Relapse to oral self-administration of morphine.

Investigated the effect of conditional environmental stimuli on morphine consumption in 117 male Sprague-Dawley rats. Ss were first trained to consume a morphine solution (increased from 1.2 mg/ml) by a forced drinking procedure spanning 235 days. Then, a period of abstinence of 81 days was given. They next received injections of morphine in 1 environment and injections of saline in a different environment (30 injections of morphine, dose increased from 5- to 40 mg/kg). At the end of this phase, the effects of conditional environmental stimuli on tolerance to the analgesic effect of 40 mg/kg morphine were examined. Consistent with previous results, analgesic tolerance was most pronounced in the context of the cues previously associated with subcutaneous morphine injections. The effects of the different environments on consumption of morphine were determined in 1- and 2-bottle tests. Findings show that, in a 2-bottle test, there was almost no consumption of the morphine solution regardless of environment. In a 1-bottle test, significantly more morphine was consumed in the drug environment than in the saline environment. Results are discussed in relation to theoretical views of the role of environmental stimuli in tolerance and drug dependence. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist LY293558 attenuates and reverses analgesic tolerance to morphine but not to delta or kappa opioids

Antagonists of the NMDA type of excitatory amino acid (EAA) receptor attenuate or reverse the development of tolerance to the analgesic effects of the mu opioid agonist morphine, the delta-1 opioid agonist DPDPE but not the kappa-1 agonist U50,488H or the kappa-3 agonist naloxone benzoylhydrazone. The role of the AMPA subtype of EAA receptor in analgesic tolerance was examined using LY293558, a selective competitive antagonist that is active after systemic administration. Administration of morphine, DPDPE, or U50,488H three times daily for 3 days according to an escalating dosing schedule resulted in analgesic tolerance as indicated by an increase in analgesic ED50 values using the tail-flick test in mice. Analgesic tolerance was attenuated when mice received a continuous subcutaneous infusion of LY293558 at doses of 30, 45 or 60 mg/kg/24 hr via an osmotic pump concurrent with the morphine treatment. Continuous subcutaneous infusion of LY293558 (45 mg/kg/24 hr) also reversed established morphine tolerance. In contrast, continuous subcutaneous infusion of the highest dose of LY293558 (60 mg/kg/24 hr) was ineffective in preventing the development of analgesic tolerance to DPDPE or U50,488H. Continuous subcutaneous infusion of LY293558 (60 mg/kg/24 hr) for 3 days protected mice from generalized convulsions produced by the selective AMPA agonist ATPA, indicating that the dosage of LY293558 that attenuated morphine tolerance was effective as an antagonist at AMPA receptors. These results demonstrate that AMPA receptors may play a role in the development and maintenance of morphine, but not DPDPE or U50,488H, analgesic tolerance.     

Behavioral contingencies modulate tolerance to discriminative stimulus effects of morphine

Experiments examined how learning processes modulate tolerance to discriminative stimulus effects of morphine. Rats were trained to discriminate saline and 3.2 mg/kg morphine, and the doses of morphine required to mimic the training dose were determined before, during and after repeated treatment with saline or high doses of morphine (10 mg/kg, b.i.d.). In one set of experiments, training was either suspended or continued with saline and the original training dose during a 2-week treatment regimen. When training was suspended, high-dose morphine treatment increased the dose of morphine required for stimulus effects approximately 3-fold. Tolerance persisted 2 days after treatment ended, but disappeared within 7 days. In contrast, continued training with saline and 3.2 mg/kg morphine during high-dose treatment both attenuated development of tolerance and transferred control to lower doses. Transfer of control to lower doses appeared conditional upon recent termination of high-dose treatment, as it disappeared within 7 days. Treatment with saline did not change the doses of morphine required for stimulus effects under either training condition. A final experiment examined whether high-dose treatment could transfer control to higher doses of morphine. The treatment dose of 10 mg/kg morphine itself was used as the training dose during a 2-week treatment regimen. The dose of morphine required for stimulus effects increased 2- to 4-fold during treatment, but quickly returned to control values when treatment ended. These results extend previous findings that conditioning and pharmacodynamic processes jointly regulate development of tolerance to discriminative effects of morphine.     

Tolerance to discriminative stimulus effects of d-amphetamine.

Chronic administration of high doses of d-amphetamine produced time-limited, surmountable tolerance to stimulus effects of d-amphetamine. 23 male Sprague-Dawley rats discriminated saline and 0.80 mg/kg d-amphetamine under fixed ratio (FR) schedules of food delivery. Suspending training and administering saline did not alter sensitivity to d-amphetamine, indicating that neither tolerance nor sensitization developed during regular training. Acute pretreatment with 3.2 mg/kg d-amphetamine did not alter the ED50 for stimulus effects of d-amphetamine. In contrast, administration of 3.2 or 6.4 mg/kg d-amphetamine, b.i.d., for 3 days or 2 weeks increased the ED50 for stimulus effects 3- to 4-fold but did not produce consistent tolerance to rate-altering effects. Tolerance to stimulus effects was surmountable, as higher doses of d-amphetamine produced full drug-lever selection in tolerant rats. Sensitivity recovered after chronic administration ended. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of dose, interdose interval, and drug-signal parameters on morphine analgesic tolerance: Implications for current theories of tolerance.

Some unique predictions of a dual-process priming model of morphine analgesic tolerance were tested. Two experiments in which morphine injections during a tolerance acquisition phase were accompanied by nociceptive testing on a hot plate, confirmed the predictions that tolerance acquisition, retention, and environment-specificity would be augmented under signaled drug conditions when low doses or long interdose intervals (IDIs) were used but not when high doses or short IDIs were used. The implications for current alternative theories of morphine tolerance are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of ibogaine on the development of tolerance to the analgesic effect of morphine.

The results of 3 experiments demonstrated that (a) 20 mg/kg ibogaine (but not 10 mg/kg), administered 30 min before morphine, attenuates the development of tolerance to the analgesic effect of morphine in rats; (b) this 20 mg/kg dose of ibogaine, if administered 5 hr before morphine, has no effect on tolerance development; and (c) a high dose of ibogaine (40 mg/kg), administered 24 hr before morphine, does not affect analgesic tolerance (despite reports that this dose of ibogaine, administered 1 day before morphine, modulates the neurochemical and reinforcing effect of the opiate, see P. Popik, R. T. Layer, & P. Skolnick, 1995). The findings are discussed in the context of suggestions that ibogaine be evaluated as a treatment for opiate dependence, and recent research indicating that ibogaine is an N-methyl-{D}-aspartate antagonist. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of stress on morphine-elicited locomotor activity in hamsters.

Two experiments were conducted to investigate the effects of stress on morphine-elicited locomotor activity in hamsters. In Experiment 1, half of the animals were habituated to handling and injection procedures (low-stress condition) and half were not (high-stress condition) prior to 6 days of testing with a low dose (2.5 mg/kg) of morphine. On the first test day, morphine elicited hyperactivity among habituated animals, whereas among nonhabituated animals morphine elicited hypoactivity. The effects of handling diminished across test days, so that on the last test day, morphine elicited hyperactivity in both habituated and nonhabituated animals. In Experiment 2, the effect of a noise stressor on activity elicited by three doses of morphine (2.5, 5.0, and 15 mg/kg) was investigated. Half of the animals were tested under conditions of low noise stress (70 dB), and half were tested under conditions of high noise stress (90 dB). Results indicated that the effects of each dose of morphine were potentiated in the high-stress relative to the low-stress condition. Both experiments demonstrated that environmental stressors can potentiate the response to exogenous opiate administration in hamsters. Moreover, the results are consistent with the hypothesis that stress induces the release of endogenous opioids which summate with exogenous opiates to determine the final effective dose. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lesions of the nucleus accumbens in rats reduce opiate reward but do not alter context-specific opiate tolerance.

Bilateral electrolytic lesions of the nucleus accumbens in rats eliminated the capacity of 10 mg/kg morphine to produce a conditioned place preference (Experiment 1). However, these lesions did not alter the capacity to establish context-specific tolerance to the analgesic effects of 5 mg/kg of morphine (Experiment 2). This latter finding indicates that rats with nucleus accumbens lesions are not impaired in associating the effects of morphine with a particular location. Thus, the failure of morphine to produce a conditioned place preference in these lesioned rats probably cannot be attributed to an inability to associate the effects of morphine with a particular chamber, i.e., the initially nonpreferred chamber. Rather, morphine may fail to establish a conditioned place preference in these rats because nucleus accumbens lesions disrupt a pathway that is critical in mediating the rewarding effects of opiates. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene

In mice lacking the nociceptin (or orphanin FQ) receptor gene, when 10 mg/kg of morphine was subcutaneously given, a potent analgesia in the tail pinch test was observed. The analgesic effect of morphine was equivalent among wild-type, heterozygous and homozygous mutant mice. When morphine was given to such mice in a dose of 10 mg/kg once per day for 5 days, wild-type and heterozygous mice showed marked tolerance or reduction in the morphine analgesia on the 5th day, while homozygous mice showed only 50% reduction in the peripheral analgesia of morphine. These findings suggest that nociceptin or its receptor plays important roles in the in vivo mechanism for the development of morphine tolerance.