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PubMed1995

Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions.

Over the last several years, compelling evidence has accumulated indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. Such neuronal plastic changes may involve activation of central nervous system excitatory amino acid (EAA) receptors, subsequent intracellular cascades including protein kinase C translocation and activation as well as nitric oxide production, leading to the functional modulation of receptor-ion channel complexes. Similar EAA receptor-mediated cellular and intracellular mechanisms have now been implicated in the development of tolerance to the analgesic effects of morphine, and a site of action involved in both hyperalgesia and morphine tolerance is likely to be in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, may be interrelated by common neural substrates that interact at the level of EAA receptor activation and related intracellular events. This view is supported by recent observations showing that thermal hyperalgesia develops when animals are made tolerant to morphine antinociception and that both hyperalgesia and reduction of the antinociceptive effects of morphine occur as a consequence of peripheral nerve injury. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.

Animals↗
PubMed1975

Uptake into brain proteins of 35S-methionine during morphine tolerance.

Effect of morphine sulfate on protein synthesis in rat brain was evaluated in tolerant and nontolerant rats. Male Wistar-Lewis rats were randomly distributed to control, tolerant and nontolerant groups. The rats were made tolerant by giving morphine sulfate (25 mg/kg b.i.d.) for either 42 or 84 days. An aqueous solution of 35S-methionine (0.5 muc/g b.w.t.) was administered i.v. Rats from each group were then sacrificed at 20 minutes, 1 hour and 2 hours after 35S-methionine. The 35S-activity in trichloroacetic acid-precipitated proteins and supernatant fractions from cortex, hypothalamus, putamen, corpus callosum, thalamus, cerebellum, kidney and liver was determined. In addition the amounts of label in lipid, saline-soluble and insoluble proteins of whole brain for tolerant and control rats were determined. The 35S-activity in brain proteins of non-tolerant rats did not differ from those of controls. The six brain areas in tolerant rats 1 and 2 hours after injection of 35S-methionine showed a 15 percent, then 30 percent increase in radioactivity (disintegrations per minute per milligram of protein). Proteins from putamen and corpus callosum had w/w 60 percent of the 35S-activity found in hypothalamus and cortex. There was no difference in 35S-activity in kidney and liver between control and tolerant rats. The radioactivity of the brain lipids was 2 percent of that found in proteins in both tolerant and control groups. Protein synthesis in morphine tolerant rat brain is significantly (P smaller than .01) increased as judged by incorporation of 35S-methionine.

Animals↗
PubMed1999

Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions.

Compelling evidence has accumulated over the last several years from our laboratory, as well as others, indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. In our laboratory, chronic constriction injury of the common sciatic nerve, a rat model of neuropathic pain, has been shown to result in activation of central nervous system excitatory amino acid receptors and subsequent intracellular cascades including protein kinase C translocation and activation, nitric oxide production, and nitric oxide-activated poly(ADP ribose) synthetase activation. Similar cellular mechanisms also have been implicated in the development of tolerance to the analgesic effects of morphine. A recently observed phenomenon, the development of "dark neurons," is associated with both chronic constriction injury and morphine tolerance. A site of action involved in both hyperalgesia and morphine tolerance is in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance may be interrelated at the level of the superficial laminae of the dorsal horn by common neural substrates that interact at the level of excitatory amino acid receptor activation and subsequent intracellular events. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.

Animals↗
PubMed1991

Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat.

To investigate the possible role of excitatory amino acids (EAAs) in the mechanisms of morphine tolerance, rats were treated either with the wide-spectrum EAA antagonist, kynurenic acid (150 mg/kg), or the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist. MK-801 (0.05 mg/kg), during a four-day induction period of morphine tolerance. Morphine was given once daily at a dose of 15 mg kg. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by both EAA antagonists. Control experiments showed that at the same doses neither acute nor chronic administration of these antagonists affected morphine analgesia itself in a manner that can explain these findings. The possible involvement of EAAs in the mechanisms of morphine tolerance is discussed.

Analgesia↗
PubMed1993

[The enkephalinase mechanisms of the resistance and tolerance to the analgesic effect of morphine in rats. Differences in the effects of naloxone in morphine-sensitive, morphine-resistant and morphine-tolerant rats].

In morphine-sensitive (s. c. 1.5 mg/kg) Wistar rats i.p. injection of 0.3 mg/kg naloxone either did not change nociception (tail-flick test) or induced hyperalgesia. In morphine-resistant rats 0.2-0.7 mg/kg naloxone injection induced analgetic effect but 1.0 mg/kg induced hyperalgesia. In morphine-sensitive rats chronic morphine administration induced the tolerance and naloxone injection evoked analgetic effect. Morphine inoculation just after naloxone analgesia was over induced analgetic effect. In morphine-resistant and -tolerant rats chronic naloxone administration induced gradual decrease and subsequent disappearance of its analgetic effect and subsequent morphine injections induced analgetic effect for some days. It is suggested that naloxone in morphine-resistant and -tolerant rats with high level of enkephalinase activity functions as its inhibitor. Chronic naloxone administration evoked progressive inhibition of enkephalinase activity that induced the morphine analgetic effect in morphine-resistant and -tolerant rats.

Analgesia↗
PubMed2003

Endothelin receptor antagonists restore morphine analgesia in morphine tolerant rats.

Several neurotransmitter mechanisms have been proposed to play a role in the development of morphine tolerance. The present study provides evidence for the first time that endothelin (ET) antagonists can restore morphine analgesia in morphine tolerant rats. Tolerance to morphine was induced by subcutaneous implantation of six morphine pellets during a 7-day period. The degree of tolerance to morphine was measured by determining analgesic response (tail-flick latency) and hyperthermic response to morphine sulfate (8 mg/kg, subcutaneously (s.c.)) in placebo and morphine pellet implanted rats. The maximal tail-flick latency in morphine pellet-vehicle treated rats (7.54 s) was significantly lower (P<0.05) when compared to placebo pellet-vehicle treated rats (10s), indicating that tolerance developed to the analgesic effect of morphine. In separate sets of experiments, ET antagonists, BQ123 (10 microg, intracerebroventricularly (i.c.v.)) and BMS182874 (50 microg, i.c.v.) were administered in placebo and morphine tolerant rats. BQ123 was injected twice daily for 7 days and once on day 8. BMS182874 was administered only on day 8. Morphine (8 mg/kg, s.c.) was administered 30min after BQ123 or BMS182874 administration. It was found that both BQ123 and BMS182874 potentiated morphine analgesia in placebo and morphine tolerant rats. BQ123 potentiated tail-flick latency by 30.0% in placebo tolerant rats and 94.5% in morphine tolerant rats compared to respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo tolerant rats and 66.7% in morphine tolerant rats. Morphine-induced hyperthermic effect was also potentiated by BQ123 and BMS182874. The duration of analgesic action was also prolonged by BQ123 and BMS182874. The effect of BMS182874 was less as compared to BQ123. BQ123 and BMS182874 are selective ET(A) receptor antagonists. Therefore, it is concluded that ET(A) receptor antagonists restore morphine analgesia in morphine tolerant rats.

Animals↗
PubMed2005

Dexamethasone modulates the development of morphine tolerance and expression of glutamate transporters in rats.

We recently demonstrated an increase in spinal cerebrospinal fluid (CSF) excitatory amino acids (EAAs) in morphine-tolerant rats after morphine challenge. The present study examined whether co-infusion of the glucocorticoid dexamethasone (DEX) co-infusion inhibited morphine tolerance and the morphine challenge-induced EAAs increase after long-term morphine infusion. Intrathecal (i.t.) catheters and one microdialysis probe were implanted to male Wistar rats. Rats were divided into four groups: i.t. morphine (15 microg/h), saline (1 microl/h), DEX (2 microg/h), or DEX (2 microg/h) plus morphine (15 microg/h) infusion for 5 days. Tail-flick responses were examined before drug infusion and daily after the start of infusion for 5 days. Moreover, on day 5 after morphine challenge (50 microg, i.t.), CSF EAAs was also measured. Rat spinal cords were removed on day 5, and prepared for Western blot analysis of different glutamate transporters (GTs). The AD50 (analgesic dose) on day 5 was 1.33 microg in saline-infused rats, 83.84 microg in morphine-tolerant rats, and 10.15 microg in DEX plus morphine co-infused rats. Single DEX (2 microg, i.t.) injection did not enhance morphine's antinociceptive effect in either naïve or morphine-tolerant rats. No difference in CSF EAA level was observed in all groups between baseline (before drug infusion) and on day 5 after tolerance developed. Surprisingly, on day 5, after morphine challenge, an increase in glutamate and aspartate (284+/-47% and 201+/-18% of basal) concentration was observed, and morphine lost its antinociceptive effect (maximum percent effect, MPE = 41+/-12%), whereas DEX/morphine co-infusion inhibited morphine-evoked EAA increase with a MPE = 97+/-2%. DEX co-infusion prevented the downregulation of glial glutamate transporters (GLAST (Glu-Asp transporter) and GLT-1 (Glu transporter-1)), but not the neuronal GT EAAC1 (excitatory amino acid carrier). Upregulation of GLT-1 was also observed (204+/-20% of basal). DEX co-infusion inhibits the morphine-challenge induced EAA increase and prevents the loss of morphine's antinociceptive effect after long-term morphine infusion.

Amino Acid Transport System X-AG↗
PubMed1983

Modification of behavioral effects of morphine, meperidine and normeperidine by naloxone and by morphine tolerance.

Lever-press responding of morphine-tolerant and nontolerant squirrel monkeys was maintained under a multiple fixed-interval 5-min, fixed-interval 5-min schedule of food or electric shock presentation. Under the multiple schedule, the first response after a 5-min interval produced either food or shock depending on the prevailing stimulus. Responding maintained by either food or shock was characterized by patterns of positively accelerated responding during the 5-min interval. Morphine (0.1-1.0 mg/kg), meperidine (0.3-10.0 mg/kg) and normeperidine (1.0-17.0 mg/kg) produced dose-related decreases in rates of responding and produced small changes in the temporal pattern of responding in monkeys not tolerant to morphine. Food- and shock-maintained responding generally were affected similarly. Naloxone (0.1-3.0 mg/kg) had no effect when given alone to nontolerant monkeys. Both morphine tolerance and naloxone administration reversed the rate-decreasing effects of morphine and shifted the morphine dose-effect function to the right. Naloxone administration and morphine tolerance also reversed the rate-decreasing effects of meperidine and normeperidine, but unlike with morphine, combinations of naloxone and meperidine or normeperidine disrupted temporal patterns of responding and, at the higher doses, increased rates of responding well above control values. Drug effects in morphine-tolerant or naloxone-treated monkeys were not dependent on the event maintaining responding as comparable local rates of responding maintained by food or shock presentation were affected similarly. It was concluded that meperidine and normeperidine possess behavioral effects in common with those of morphine as well as pronounced non-morphine-like effects which are revealed by interference with the receptors upon which morphine acts.

Animals↗
PubMed1990

Plasma beta-endorphin and cortisol levels in morphine-tolerant rats and in naloxone-induced withdrawal.

The relationship between morphine tolerance and pituitary-adrenocortical activity was examined. In rats made tolerant to morphine by implantation of morphine-containing pellets, there was a significant reduction in plasma levels of beta-endorphin-like immunoreactivity (beta-END-LI), whereas no significant changes in cortisol levels were seen. Naloxone treatment induced an increase in plasma beta-END-LI and cortisol levels in morphine-tolerant animals. Additionally, acute morphine administration induced an increase in plasma levels of beta-END-LI and cortisol, an effect which was prevented by naloxone. These results are consistent with an increased release of pro-opiomelanocortin-derived peptides after acute morphine and with a decreased release of these peptides in tolerant rats, and suggest that opioid peptides play an important role in the regulation of pituitary-adrenocortical function.

Animals↗
PubMed2004

The effects of intrathecal gabapentin on spinal morphine tolerance in the rat tail-flick and paw pressure tests.

Analgesic tolerance to opioids has been described in both experimental and clinical conditions and may limit the clinical utility of these drugs. We have previously shown that systemic gabapentin (GBP), a non-opioid drug, prevents and reverses tolerance to systemic morphine in the rat. In this study, we investigated the effect of intrathecal GBP on spinal morphine tolerance. Studied rats were given 7 days of intrathecal injections with saline (10 microL), GBP (300 microg), morphine (15 microg), or a GBP-morphine combination, and analgesic testing using tail-flick and paw-pressure tests was conducted before and 30 min after the drug injection. On Day 8, an antinociceptive dose-response curve was constructed and the 50% effective dose (ED(50)) values for morphine (given alone) were calculated for each study group. Coinjection of GBP with morphine blocked the development of tolerance, as shown by the preservation of morphine analgesia over 7 days as well as by a concomitant decrease in ED(50) values on Day 8, as compared with the morphine-alone group. Although additive analgesia over Days 1-7 cannot be ruled out, ED(50) reductions in the GBP-morphine combination group indeed suggest some suppression of tolerance. These data support previous evidence that GBP prevents opioid tolerance and, more specifically, indicate that intrathecal GBP prevents the development of spinal opioid tolerance. Future studies are required to examine the respective roles of supraspinal and peripheral sites of GBP-morphine interaction and to investigate the mechanisms underlying the action of GBP on opioid tolerance.

Acetates↗
PubMed1994

Effects of morphine tolerance and abstinence on cellular immune function.

Female B6C3F1 mice were rendered tolerant-dependent on morphine by a combination of injections and pellet implantation. Mice were injected with morphine sulfate (20 mg/kg, s.c.) twice a day on day 1. On day 2, they were implanted s.c. with a 75 mg morphine pellet for 3 days. On day 5, the pellets were either left intact (tolerant) or removed 8 h prior (abstinent) to carrying out the immune function tests. A high degree of tolerance to the analgesic and hypothermic effect of morphine developed as a result of this procedure. Similarly, physical dependence also developed as evidenced by the signs of the abrupt and naltrexone-precipitated abstinence syndrome. Implantation with morphine pellets resulted in a profound, statistically significant reduction in spleen and thymus weight and cellularities, with the greatest degree of reduction noted in abstinent animals. Morphine tolerance was associated with suppressed B-cell proliferation following in vitro stimulation, as well as interleukin-2 (IL-2) and interleukin-4 production by T-cells. NK cell activity was significantly reduced in morphine-tolerant, but not in morphine-abstinent, mice following a 24 h incubation in the presence or absence of IL-2. In comparison, the in vitro induction of cytotoxic T-cells was significantly depressed in morphine-abstinent, but not morphine-tolerant, animals. Exposure to morphine apparently had limited effect on macrophage function as assessed by production of tumor necrosis factor. These studies demonstrate a differential effect on immune effector and regulatory mechanisms in morphine tolerance and abstinence processes.

Animals↗
PubMed2006

[Differential reversal effect of intrathecal bovine adrenal medulla peptide 22 on morphine tolerance in rats].

Bovine adrenal medulla 22 (BAM22), an endogenous opioid peptide, is one of the cleavage products of proenkephalin A. It potently activates opioid receptors and sensory neuron-specific receptor (SNSR). The present study was aimed at investigating the effect of BAM22 on morphine tolerance. Intrathecal (i.t.) administration of morphine for 7 d produced morphine tolerance in rats. Then the rats were divided into three groups in which morphine, saline or BAM22 were administered i.t., respectively, on day 8, and morphine was given to all of the animals on day 9. It was found that morphine administered on day 9 resumed antinociceptive effects in BAM22 group, but not in saline or morphine group. The potency of morphine in BAM22 group was 48.5% of the maximal possible effect (MPE) detected by paw withdrawal test and the antinociception persisted for approximately 1 h. Following the similar treatment, morphine administered on day 9 reduced nocifensive behaviors by 3.2 min and 24 min in BAM22 group in the first and second phases, in the formalin test, respectively. The decreases were 45% and 82% of the corresponding values observed in saline group. Furthermore, following the treatment with BAM22 (10 nmol) on day 8 in morphine-tolerance rats, morphine administered on day 9 decreased the expressions of the heat-evoked c-Fos-like immunoreactivity (FLI) protein by approximately 80% in laminae I-II, III-IV and V-VI in the spinal cord at L4-L5 compared with that in saline or morphine group. The present study provided evidence at behavioral and cellular levels showing that BAM22 resumed antinociception of morphine. The results that the reversal effect of BAM22 on morphine tolerance was more efficient in persistent pain model than in acute pain may indicate that BAM22 differentially modulates morphine tolerance. The present study suggests that SNSR is involved in the modulation of morphine tolerance.

Animals↗
PubMed1994

Dynorphin A-(1-13)-morphine interactions: quantitative and qualitative EEG properties differ in morphine-naive vs. morphine-tolerant rats.

The effects of dynorphin A-(1-13) on cumulative IV morphine-induced EEG and EEG power spectra were studied in naive and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with cortical EEG electrodes and permanent indwelling ICV and IV cannulae. In naive rats, dynorphin A-(1-13) quantitatively decreased cumulative IV morphine-induced EEG spectral power as well as qualitatively shifting the relative distribution of spectral power to predominantly faster frequencies. In morphine-tolerant rats, the quantitative and qualitative EEG properties were identical to those in dynorphin A-(1-13) pretreated morphine-naive rats. Thus, dynorphin A-(1-13) pretreatment apparently produced instantaneous acute morphine tolerance. Furthermore, in morphine-tolerant rats, dynorphin A-(1-13) pretreatment quantitatively increased morphine-induced EEG power without qualitatively changing the relative distribution of EEG spectral power. This latter effect may be due to a summation of increased endogenous levels of dynorphin A-(1-13) associated with the development of morphine tolerance and the experimentally administered dynorphin A-(1-13). These results indicate that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. That is, quantitative changes may reflect the number of receptors that are activated, while qualitative changes may reflect the nature of the receptor-effector coupling.

Animals↗
PubMed1993

Lack of the development of morphine tolerance in experimental amnesia: role of arginine vasopressin.

The development of tolerance to morphine analgesia in amnesic model mice and the role of arginine vasopressin (AVP) in the underlying mechanism was examined. Hypoxia, brain ischemia, scopolamine and electroconvulsive shock (ECS) manipulation caused amnesia in the step-through type passive avoidance learning test performed at 24 h after the training trial. The amnesic state lasted for at least 3 days and recovered to naive control level on the 20th day after each manipulation. In all amnesic groups, radioimmunoassayable AVP content in hypothalamus was decreased, in particular, the reduction was significant in hypoxia and ischemic induced amnesic animals, then recovered to the control level by 20 days after each treatment. Daily morphine, 10 mg/kg, s.c. easily resulted in the development of tolerance to the analgesic effect in control animals; however, such treatment failed to develop tolerance in amnesic model animals, leaving the analgesic effect unchanged to the control levels. Daily pretreatment with i.c.v. AVP, dose-dependently reinstated the development of tolerance in amnesic model mice. When morphine injection was started from 20 days after the amnesia inducing treatment, tolerance developed as in a similar pattern as in control animals. Thus, amnesic model mice are deficient in brain AVP levels, and consequently, a certain level of AVP in the hypothalamus is required for maintaining the normal function such as the development of tolerance to morphine and the recovery from amnesia.

Amnesia↗
PubMed1983

Relationship of dose to morphine tolerance in the chick embryo.

Morphine tolerance and dependence can be produced in chick embryos by injecting 20 mg/kg into the airspace of the egg daily for 4 days beginning on incubation day 12. The experiments in this report examined the production of tolerance with lower doses of morphine (2.5, 5.0 and 10.0 mg/kg). Treatment of embryos for 4 days did not produce tolerance on day 16 when the challenge dose was the same as the dose used for pretreatment and when activity was recorded at only one time after injection. Further studies measuring activity at multiple time-points and/or utilizing a lower challenge dose indicated that tolerance was present. Studies of activity after 4 or 8 days of pretreatment revealed a dose-effect relationship. Pretreatment with 2.5 mg/kg produced a lesser degree of tolerance than that produced by the higher pretreatment doses. These embryos were tolerant on day 16 after four injections but not on day 19 after eight injections, due perhaps to more rapid metabolism of morphine with age. There were no differences between the responses of the 5.0 and 10.0 mg/kg groups to morphine challenge. While both of these doses produced tolerance to a low challenge dose of morphine by day 16, pretreatment at doses higher than 10.0 mg/kg was necessary for production of tolerance to high doses.

Animals↗
PubMed1980

The effects of cholinergic compounds on the development of morphine tolerance, dependence and increased naloxone potency in mice.

The effects of chronic treatment with morphine and cholinergic compounds on the development of morphine tolerance, physical dependence and increased naloxone potency were studied. Using the abdominal constriction method, it was shown that morphine tolerance was apparent after s.c. administration of morphine 20.0 mg/kg three times a day for four days. It was found that, in animals which showed a low degree of morphine tolerance, the naloxone potency was similar to that determined in mice which had been pretreated with only a single dose of morphine which causes no measurable tolerance. Thus, the development of increased naloxone potency and tolerance to morphine do not parallel each other. In addition, while atropine inhibited, and anti-cholinesterase drugs enhanced, the development of increased naloxone potency caused by morphine treatment they had no or little effect on the development of morphine tolerance. Furthermore, chronic treatment with cholinergic agonists reduced, while muscarinic antagonist enhanced, the development of physical dependence on morphine as assessed by withdrawal jumping and body weight loss. It is concluded that the increased potency of naloxone in antagonising the antinociceptive effect of morphine can be dissociated from the development of tolerance to, and physical dependence on, morphine in mice.

Animals↗
PubMed2006

Inhibition of morphine tolerance by processed Aconiti tuber is mediated by kappa-opioid receptors.

Previously, we found that processed Aconiti tuber (PAT) could inhibit morphine tolerance in mice. In the present study, we investigated mechanisms underlying this effect. Mice received subcutaneous (s.c.) morphine (10 mg/kg) and oral PAT at a subanalgesic dose (0.3 g/kg), once a day for 12 days. Additional PAT-treated groups received morphine and PAT, at 120 min after pretreatment with s.c. clocinnamox mesylate (C-CAM) (0.5 mg/kg), or nor-binaltorphimine (nor-BNI) (5 mg/kg). The antinociceptive effect was assessed with the tail pressure test, at 60 min after the daily s.c. morphine injections were given. In the placebo-treated group, repeated morphine injections caused morphine tolerance, and morphine antinociception was abolished by day 6, whereas in PAT-treated groups, significant antinociception was maintained until day 12, suggesting that PAT inhibited morphine tolerance, thereby sustaining morphine antinociception. C-CAM, a selective mu-opioid receptor (MOR) antagonist, blocked morphine antinociception whereas nor-BNI, a selective kappa-opioid receptor (KOR) antagonist, did not. However, both C-CAM and nor-BNI could block the antinociception maintained by the morphine-PAT combination. Results of the study suggested that chronic treatment with PAT at a subanalgesic dose maintained MOR-mediated morphine antinociception by attenuating development of morphine tolerance, and that this tolerance-attenuating effect of PAT was mediated by KOR.

Aconitum↗