Extinction of tolerance to the analgesic effect of morphine: Intracerebroventricular administration and effects of stress.

Previous research demonstrated that tolerance to the analgesic effect of morphine in rats is attenuated by administrations of a placebo in the context of drug-associated cues. Such apparent extinction of tolerance has been interpreted as support for a Pavlovian conditioning model of tolerance. Recently, it has been suggested that these findings are attributable to stress, induced during placebo sessions and augmenting the analgesic effect of morphine (rather than to Pavlovian extinction). Our results indicate that placebo sessions actually attenuate tolerance by extinguishing the association between predrug cues and the systemic effects of the drug. In addition, the results indicate that conditioning contributes to analgesic tolerance when morphine is administered intracerebroventricularly, which suggests that conditional alterations within the central nervous system mediate such tolerance. This contrasts with alternative suggestions that conditional alterations in drug distribution or metabolism mediate the effects of conditioning manipulations on tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Overshadowing effects in the stimulus control of morphine analgesic tolerance.

Attempted to replicate previous demonstrations of classical conditioning of morphine analgesic tolerance and to determine whether stimulus overshadowing effects might explain previous conflicting findings. In Exp I, 8 groups of male Sprague-Dawley rats received a series of 10 morphine (5 mg/kg) and/or saline injections, differing only with respect to the contingency between a compound visual-auditory CS and the substance injected. When tested for analgesic responding to morphine in the presence of the compound CS, only those groups for which the CS and morphine injections were paired during the acquisition sequence evidenced tolerance. In Exp II, tolerant Ss were tested in the presence of 1 component of the compound CS. When a loud tone (85 db) was used in the compound, less analgesic tolerance was elicited later by the weaker visual stimulus alone. This differential stimulus control of the analgesic response suggests that overshadowing may contribute to failures to replicate conditioned morphine tolerance. It is possible that internal morphine-produced stimuli may overshadow external cues. (18 ref) (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)     

Increases in protein kinase C gamma immunoreactivity in the spinal cord of rats associated with tolerance to the analgesic effects of morphine

Our previous studies have indicated a critical role of protein kinase C (PKC) in intracellular mechanisms of tolerance to morphine analgesia. In the present experiments, we examined (1) the cellular distribution of a PKC isoform (PKC gamma) in the spinal cord dorsal horn of rats associated with morphine tolerance by utilizing an immunocytochemical method and (2) the effects of the N-methyl-D-aspartate receptor antagonist MK-801 on tolerance-associated PKC gamma changes. In association with the development of tolerance to morphine analgesia induced by once daily intrathecal administration of 10 micrograms morphine for eight days, PKC gamma immunoreactivity was clearly increased in the spinal cord dorsal horn of these same rats. Within the spinal cord dorsal horn of morphine tolerant rats, there were significantly more PKC gamma immunostained neurons in laminae I-II than in laminae III-IV and V-VI. Such PKC gamma immunostaining was observed primarily in neuronal somata indicating a postsynaptic site of PKC gamma increases. Moreover, both the development of morphine tolerance and the increase in PKC gamma immunoreactivity were prevented by co-administration of morphine with 10 nmol MK-801 between Day 2 and Day 7 of the eight day treatment schedule. In contrast, PKC gamma immunoreactivity was not increased in rats receiving a single i.t. administration of 10 micrograms morphine on Day 8, nor did repeated treatment with 10 nmol MK-801 alone change baseline levels of PKC gamma immunoreactivity. These results provide further evidence for the involvement of PKC in NMDA receptor-mediated mechanisms of morphine tolerance.     

Dizocilpine (MK-801) blocks tolerance to the analgesic but not to the hyperthermic effect of morphine in the rat

The effect of dizocilpine (MK-801), an N-methyl-D-aspartate receptor antagonist, on the development of tolerance to the analgesic and hyperthermic effects of morphine was determined in the rat. Tolerance to morphine in male Sprague-Dawley rats was induced by implanting subcutaneously 6 morphine pellets during a 7-day period. Two schedules of intraperitoneal injections of MK-801 were used. In one, the drug was injected once a day, and in the other it was injected twice a day. The doses of MK-801 were 0.03, 0.1 and 0.3 mg/kg. In the treatment once a day, MK-801 blocked the development of tolerance to the analgesic effect of morphine, but there was no dose-dependent effect. In the treatment twice a day, MK-801 produced a dose-dependent inhibition of tolerance to the analgesic effect of morphine. Higher doses of MK-801 produced high mortality. MK-801 given once a day or twice a day failed to affect the tolerance to the hyperthermic effect of morphine. In both schedules of MK-801 treatment, the highest dose of MK-801 resulted in high mortality. It is concluded that MK-801 is selective in blocking the tolerance to the analgesic effect of morphine in the rat.     

Anticipatory hyperexcitability and tolerance to the narcotizing effect of morphine in the rat.

Examined the role of Pavlovian conditioning in tolerance to the narcotizing effect of a high dose of morphine in 32 male albino Sprague-Dawley rats. Initially, 2 groups received 9 injections of morphine (40 mg/kg), and 2 groups received 9 injections of saline. One group administered each substance was injected in 1 of 2 distinctive environments: the animal colony or a distinctive room. Subsequently, Ss in all groups received 5 morphine injections in the distinctive room. Analyses of videotape records of postinjection behavior indicated that Ss tested in the presence of the usual predrug cues were more tolerant to the narcotizing effect of morphine than Ss tested with cues different from those previously associated with morphine. In addition, Ss tested with the usual predrug cues exhibited more anticipatory "hyperexcitable" behavior than Ss tested in the absence of the usual predrug cues. Results provide further evidence that compensatory pharmacological conditional responses partially mediate tolerance and suggest that these drug-anticipatory responses contribute to so-called "withdrawal symptoms." (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential involvement of enkephalins in analgesic tolerance, locomotor sensitization, and conditioned place preference induced by morphine.

In this study, the authors investigated the role of enkephalins in morphine-induced conditioned place preference, locomotor sensitization, and analgesic tolerance. Both preproenkephalin wild type (ppENK [+/+]) and knockout (ppENK [-/-]) mice showed similar preference for the morphine-paired chamber over the vehicle-paired chamber, indicating morphine induced comparable conditioned place preference in ppENK (+/+) and ppENK (-/-) mice. Sensitization developed to the motor stimulatory action of morphine after its repeated administration, but the magnitude of this response was not altered in ppENK (-/-) mice. However, as shown previously, ppENK (-/-) mice displayed blunted morphine analgesic tolerance. Taken together, the results suggest that enkephalins may be important for the development of analgesic tolerance but not for conditioned place preference or behavioral sensitization induced by morphine. (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)     

Interaction of intrathecally infused morphine and lidocaine in rats (part II): effects on the development of tolerance to morphine

BACKGROUND: There has been little information regarding the effects of local anesthetics on tolerance to opioids, although chronic use of combination of opioids and local anesthetics is popular for pain control. This study was designed to examine the effects of lidocaine on morphine tolerance to somatic and visceral antinociception. METHODS: Rats received a continuous intrathecal infusion of morphine (0.3-10 microg x kg(-1) x h(-1)), lidocaine (30-1000 microg x kg(-1). h(-1)), a combination of those, or saline. After 6- day infusion, intrathecal morphine challenge test (5 microg/10 microl) was performed, and time-response curve was constructed to assess the magnitude of tolerance. The tail flick (TF) test and colorectal distension (CD) test were used to measure somatic and visceral antinociceptive effects, respectively. RESULTS: Antinociceptive effects in the TF and CD tests caused by morphine challenge were reduced (P < 0.01) in the morphine infused groups. The magnitude of the tolerance was inversely associated with the amount of morphine infused. Lidocaine infusion induced no different change in the morphine challenge test from that seen in the saline infusion group. Development of tolerance was greater in morphine 3 microg x kg(-1) h(-1) than in morphine 0.75 microg x kg(-1) x h(-1) + lidocaine 150 microg x kg(-1) x h(-1) despite their similar antinociceptive effects during intrathecal infusion. The infusion of a low dose of morphine (0.3 microg kg(-1) x h(-1)) did not reduce the antinociceptive effects in the challenge test. CONCLUSION: Lidocaine in combination with morphine does not reduce tolerance to morphine nor develop cross-tolerance. The intrathecal infusion of morphine induced tolerance to somatic and visceral antinociception in a dose-dependent fashion.     

The role of cholecystokinin in conditional compensatory responding and morphine tolerance in rats.

As elaborated in the conditioning analysis of tolerance, cues present at the time of drug administration become associated with the drug effect. A particularly salient cue that may become associated with the drug effect is the pharmacological drug-onset cue inherent to drug administration. Drug-associated cues contribute to tolerance by eliciting a conditional compensatory response that attenuates the drug effect. For example, the early drug effect, having been paired with the subsequent larger drug effect, may elicit the release of antiopioid peptides that counter opioid effects. The role of a putative antiopioid peptide, cholecystokinin-8 (CCK), in the associative mechanisms of opiate tolerance was evaluated. The results of these experiments suggest that a CCK2 receptor antagonist attenuates both the expression of opiate tolerance and the conditional compensatory response hypothesized to mediate such tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects

OBJECTIVE: Codeine O-demethylation to morphine is catalysed by the genetic polymorphic sparteine oxygenase (CYP2D6). The objective of the present study was to assess the analgesic effect of codeine on different types of experimental pain in relation to sparteine phenotype. METHODS: Fourteen extensive (EMs) and 14 poor metabolizers (PMs) of sparteine completed a randomized, double-blind, three-way, cross-over study with a single oral dose of codeine (75 or 100 mg) against morphine (20 or 30 mg) and placebo. Pain tests performed before and 1, 2, 3, and 4 h after medication included the cold pressor test and pain thresholds for heat and pressure stimulation. Adverse effects were rated by a structured interview. RESULTS: After morphine, morphine and morphine-6-glucuronide were present in equal amounts in plasma of PMs and EMs. After codeine, neither morphine nor morphine-6-glucuronide could be detected in 13 of the 14 PMs, whereas at least one of the compounds could be detected in all EMs. Peak pain and discomfort rated on a VAS scale during the cold pressor test were significantly reduced by morphine in both EMs and PMs, with a median peak change of 8.5 and 7.0 mm, respectively, for peak pain, and 11.5 and 15.5 mm, respectively, for discomfort. Codeine only reduced these pain measures significantly in EMs, with a median peak change of 5.5 mm for peak pain and 10.5 mm for discomfort. Pain detection and tolerance thresholds to heat and pressure were not consistently altered by either morphine or codeine. In PMs, adverse effects were significantly more pronounced on morphine than on codeine and only showed a slight difference between codeine and placebo. In EMs, there was no difference between codeine and morphine and more pronounced adverse effects on both drugs as compared to placebo. CONCLUSION: This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.     

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)     

Tolerance to the antinociceptive effect of morphine in spinally transected rats.

Examined the effect of a spinal transection (ST) on morphine (MOR)-induced tolerance in rats with the tail withdrawal reflex (tail flick; TF), elicited by noxious thermal stimulation. Intact Ss became tolerant to sc MOR injections if they were tested on the TF after each injection. MOR administration alone did not produce tolerance; TF tests alone did, although not always to a significant extent. However, when MOR only, TF tests only, or both were administered prior to ST (acute spinal Ss), all groups were tolerant when tested 1 day after spinalization. When the same treatments were administered to Ss 3 wks after ST (chronic spinal Ss), neither MOR nor TF tests alone produced tolerance. Chronic spinal Ss became tolerant only if they were tested after each injection. Results suggest that tolerance develops at the spinal cord as a result of either chronic opiate exposure or performance of the nociceptive response, but in intact Ss, tolerance is inhibited or suppressed by a supraspinal action of MOR. Results also suggest that such tolerance is mediated by descending input or that ST produced intrinsic changes in the spinal cord that preclude the development of tolerance induced only by opiate or behavioral stimulation. (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)     

The analgesic effect of fentanyl, morphine, meperidine, and lidocaine in the peripheral veins: a comparative study

It has been reported that in patients with inflammatory bowel disease (IBD), the airways are involved, and a number of clinical manifestations have been described. The aim of this study was to investigate the function of the small airways in IBD. Thirty patients with IBD (mean age, 47 yr), 12 with Crohn's disease and 18 with ulcerative colitis, were studied and compared with a control group of 16 normal subjects. Maximal expiratory flow-volume curves were performed breathing room air and a mixture of 80% helium, 20% oxygen. The differences of flows at 50% of FVC (delta Vmax50) and the volume of equal flows (Visov) were calculated as indices of small airways function. In addition, spirometry, lung volumes, and diffusing capacity were measured. Visov was statistically significantly greater in patients with either CD or UC than in control subjects (x +/- SD) (24.99 +/- 1.35 and 25.95 +/- 1.5 versus 20.1 +/- 1.39), (p < 0.01 and p < 0.001, respectively). A reduction in TL(CO) was noticed in the active stage of the disease in both groups of patients (p < 0.05). This may indicate that lung parenchyma is also involved in active IBD. Our results suggest that the function of the small airways and diffusion capacity of the lungs are affected in patients with IBD.     

Conditioned increases in locomotor activity produced with morphine as an unconditioned stimulus, and the relation of conditioning to acute morphine effect and tolerance.

In 5 experiments with 164 male Wistar rats, Ss administered morphine (5 mg/kg, sc) during each of several daily sessions in an open field showed an increase in locomotor activity. Since increases were not observed in Ss given morphine in a different environment (home cage) and saline in the open field, it is concluded that they were due to conditioning. Increases in activity were retained over a 7-day rest period; they were also produced when a 2nd opiate (5 μg/kg etorphine) was substituted for morphine, were not seen when 2 mg/kg naloxone (ip) was administered during treatment, and were present in Ss showing tolerance to opiate-produced hypoactivity. Morphine's direct effect on activity is believed to have a biphasic dose–response curve; therefore, the relation of dose to conditioning was also studied. Increases in activity were the only conditioned behaviors observed; they were present only at the higher doses (16, 4, and 1 vs .25, .065, and 0 mg/kg), and they occurred whether or not the dose was associated with unconditioned hypoactivity. Discussion deals with the relation of conditioning and morphine tolerance, the question of whether the UCS of morphine conditioning is a compensatory or a direct effect of morphine, and the similarity of conditioned increases in activity produced by morphine and by other reinforcing stimuli. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Procedures that produce context-specific tolerance to morphine in rats also produce context-specific withdrawal.

Rats previously injected with morphine in the presence of a distinct environment (paired animals) were more tolerant to the analgesic effects of morphine in that environment than were rats previously injected with morphine in another environment (unpaired animals). When injected with saline instead of morphine in the distinct environment, paired animals were more reactive to pain (hyperalgesic) than unpaired animals, but no more reactive to pain than animals never given morphine. More important, the paired animals also exhibited more withdrawal symptoms (wet dog shakes, genital licking, circling, rearing, and defecation) during abstinence and naltrexone-precipitated withdrawal in the distinct environment than did the unpaired and saline animals. Thus, procedures that are capable of providing context-specific opiate tolerance are also capable pf producing context-specific opiate withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neural mechanisms of tolerance to the effects of cocaine

Chronic use of cocaine in high doses can produce tolerance as assessed by various behavioral, neurochemical, cellular and molecular measures in specific brain regions. Tolerance to cocaine is indicated by drug discrimination and intracranial self-stimulation models, which show the development of tolerance after approximately 1 week of frequent cocaine treatment, with recovery after a similar period of cocaine abstinence. Tolerance to the reinforcing properties of cocaine depends on dose, duration and frequency of cocaine self-administered by experimental animal or human subjects. The mechanism underlying this effect may involve an absolute or relative attenuation of dopamine response to cocaine challenge after frequent or repeated treatment in the nucleus accumbens (NAc). Similarly, afferent and efferent NAc circuits exhibit reduced metabolic activity, which lasts throughout the early period of withdrawal following repeated treatment. Attenuation of immediate early gene response also occurs, which might be related to a functional desensitization of dopamine D1-like receptors. Furthermore, intracellular adaptive responses to chronic cocaine exposure induce striatal dynorphin expression decreasing the behavioral potency of subsequent drug treatment. Thus, a combination of various pharmacodynamic mechanisms and the attenuation of dopamine response induced by sufficient dose, duration and frequency of cocaine exposure ultimately invoke the transient development of tolerance to the reinforcing effects of cocaine.     

Learning and tolerance to the intake suppressive effect of cholecystokinin in rats.

Experiments were conducted to evaluate the contribution of conditioning to tolerance to the meal suppressive effect of cholecystokinin (CCK). The results indicate that (1) tolerance was contingent (the rat had to eat in conjunction with drug administration for tolerance to the meal suppressive effect to develop), (2) tolerance was displayed only in the context of environmental cues previously associated with CCK, (3) CCK-tolerant rats overate when presented with cues previously associated with the peptide, and (4) CCK tolerance displayed latent inhibition. The results are consistent with C. X. Poulos and H. Cappell's (1991) homeostatic theory of tolerance, as well as with the results of other experiments indicating that conditioning contributes to tolerance to many effects of a variety of drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cortical potentials evoked by tooth pulp stimulation differentiate between the analgesic and sedative effects of morphine in awake rats

This study was undertaken to determine whether the cortical potential (CEP) evoked by noxious electrical stimulation of the incisor tooth pulp can be used to measure analgesia in the presence of sedation in the awake rat. Changes in the CEP produced by morphine (5, 10 and 20 mg/kg s.c.), an opioid analgesic with sedative effects, were compared with those produced by droperidol (1.25 mg/kg s.c.), a neuroleptic agent with no analgesic activity. Both drugs had similar small effects on CEP latency. However, whereas morphine produced a dose-related decrease in amplitude and area under the curve, particularly in the earliest component of the CEP, droperidol produced an increase in amplitude and area under the curve. Naloxone (0.5-2 mg/kg s.c.) reversed all effects of morphine. Similar CEPs could be evoked by electrical stimulation of the tooth pulp or surrounding gingiva in lightly anesthetized rats. However, the tooth pulp stimulation-evoked CEP was unchanged after anesthesia of the gingiva with lidocaine, and the gingiva-evoked CEP was unchanged after anesthesia of the tooth pulp. Therefore, stimulation of the rat's incisor can selectively activate intrapulpal fibers, which are sufficient to generate a CEP. This CEP is an indicator of nociception which can be used to distinguish the analgesic effects of drugs such as morphine from their sedative effects.