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PubMed1986

[Changes in the properties of brain opiate receptors during the development of morphine tolerance in rats].

The effects of prolonged administration of morphine on the properties of opiate receptors of rat brain were studied. For this purpose the isotherms of binding of labeled mu-, delta-, and chi-ligands--morphine, D-Ala2, D-Leu5-enkephalin and ethylketocyclazocine--with brain membrane preparations of morphine-tolerant rats as well as those of control animals were analyzed. For quantitative determination of dissociation constants of the ligand-receptor complexes (K) and receptor concentrations ([Q]), the difference and simulation methods were used. It was shown that the values of K and [Q] vary within broad ranges in individual animals, whereas the individual variations of the [Q]/[K] ratios in controls or in morphine-tolerant rats are not so significant. This suggests [Q]/K to be one of the basic criteria for a comparison of properties of opiate receptors in different groups of animals. The use of this criterion and of the simulation method demonstrated that the development of tolerance causes changes in the properties of delta-receptors (the [Q]/K ratio decreases by greater than 50%). Unlike delta-receptors, the tolerance has no appreciable effect on the properties of mu- or chi-receptors or on the superhigh affinity binding sites of the ligands tested.

Animals↗
PubMed1992

Clonidine inhibition of norepinephrine release from normal and morphine-tolerant guinea pig cortical slices.

Endogenous norepinephrine (NE) release in cerebral cortex slices taken from normal and morphine-tolerant guinea pigs was measured by HPLC. In normal slices, a linear relationship was found between electrically evoked NE release and the log of the frequency of stimulation in the range of 1-20 Hz. The efficiency of the alpha 2-mediated autofeedback was tested by adding the alpha 2-agonist clonidine and the alpha 2 agonist idazoxan. NE release was dose-dependently reduced by clonidine (1 nmol/L-1 mumol/L) and increased by idazoxan (10-100 nmol/L). The inhibition by clonidine was significantly greater at 1 Hz than at 3 Hz, whereas the absolute increase in NE release induced by idazoxan was greater at 3 Hz than at 1 Hz. Morphine at 1 mumol/L (a concentration per se ineffective) shifted to the left the clonidine concentrations able to inhibit NE release at 3 and 1 Hz (1-10 nmol/L), but at both frequencies, the opiate reduced the maximal inhibition induced by clonidine at 1 mumol/L. In slices taken from morphine-tolerant guinea pigs (in the presence of morphine at 1 mumol/L), clonidine (1 nmol/L-1 mumol/L) was ineffective at the stimulation rate of 3 Hz, but it was more active than in normal slices at 1 Hz. Such a response pattern suggests a reduced availability of alpha 2 receptors and an increase in their sensitivity to clonidine. However, chronic morphine treatment did not influence the physiological autoinhibition because the increase in NE release elicited by idazoxan (10-100 nmol/L) at 1 and 3 Hz was the same in normal and in "morphine-tolerant" slices.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed2000

[Increased expression of formalin-induced Fos and NADPH-d positive neurons in the spinal cord of morphine-tolerant rats].

Fos immunocytochemistry, NADPH-d histochemistry and Fos/NADPH-d double-labeling method were used to study the changes in formalin-induced Fos, NADPH-d positive and Fos/NADPH-d double-labeled neurons in the spinal cord of morphine-tolerant rats. Formalin-induced Fos-like immunoreactivity (Fos-LI) was located in the superficial laminae and neck of ipsilateral spinal cord. Acute administration of morphine decreased the expression of Fos-LI in non-tolerant rats, while the expression of Fos-LI was significantly increased in morphine-tolerant rats. Fos-LI was distributed not only in the whole laminae of the ipsilateral spinal cord but also in the contralateral spinal cord. Acute administration of morphine was ineffective in decreasing the expression of Fos-LI in morphine-tolerant rats. Morphine tolerance increased the expression of formalin-induced NADPH-d positive neurons in the superficial laminae of spinal dorsal horn. A few formalin-induced Fos/NADPH-d double-labeled neurons were detected in the superficial laminae of spinal dorsal horn of non-tolerant rats. In morphine-tolerant rats, on the other hand, formalin-induced Fos/NADPH-d double-labeled neurons were increased and distributed in the whole laminae of the ipsilateral spinal cord and the contralateral superficial spinal cord. It is suggested that NO is involved in the increase of formalin-induced Fos-LI in the spinal cord of morphine-tolerant rats and may play an important role in the development of morphine tolerance.

Animals↗
PubMed2005

Alterations in the substance P-induced anti-nociception in the central nervous system of rats after morphine tolerance.

The present study investigated the alteration in intracerebroventricular administration of substance P-induced anti-nociception after morphine tolerance in rats. The nociceptive response latencies to noxious thermal and mechanical stimulation increased significantly after intracerebroventricular administration of SP in normal rats. The SP-induced anti-nociception decreased significantly in morphine-tolerant rats than that in opioid naive rats. The results demonstrated that SP induced significant anti-nociceptive effects in the brain in normal rats, and the SP-induced anti-nociception was attenuated significantly in morphine-tolerant rats than that in opioid naive rats, indicating an alteration in SP-induced anti-nociception in the brain after chronic morphine treatments.

Adaptation, Physiological↗
PubMed1986

Modification of morphine tolerance by behavioral variables.

These experiments assessed whether the opportunity to perform a target operant in the presence of morphine would alter the development of behavioral tolerance. Morphine tolerance was assessed in rats responding under a fixed-ratio 30 schedule of food delivery. Separate groups of rats were administered 10 mg/kg of morphine either pre- or postsession for 9 weeks. The degree of drug tolerance was assessed by determining cumulative dose-response functions for morphine before, during and after chronic administration. Three to 4-fold tolerance to the rate-decreasing effects of morphine developed in rats receiving morphine presession, whereas no tolerance developed in rats receiving an equal dose of morphine postsession. Morphine sensitivity returned to initial values 4 weeks after termination of chronic administration. Eight weeks after termination of chronic administration, the drug-daily session relationship was reversed and the rats were re-exposed to 10 mg/kg of morphine for 9 additional weeks. There were fewer differences between groups receiving morphine pre- or postsession during this second chronic administration phase. During chronic administration of morphine, the dose of naloxone required to suppress response rates decreased 100-fold in rats receiving morphine presession, but only 10-fold in rats receiving morphine postsession. In contrast, chronic administration of morphine did not alter the rate-decreasing effects of the nonopioids d-amphetamine, ketamine or pentobarbital. These experiments suggest that reinforcement of an operant response in the presence of morphine promoted the development of pharmacologically specific behavioral tolerance to morphine.

Animals↗
PubMed2006

Sex differences and role of gonadal hormones on glutamate level in the nucleus accumbens in morphine tolerant rats: a microdialysis study.

Sex differences are observed in the development of tolerance to the antinociceptive effect of opioid drugs such as morphine, but the precise underlying mechanism remains unclear. There are evidences about the interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. We examined the sex differences and the role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. A microdialysis probe was implanted into the left nucleus accumbens core of rats and CSF (cerebrospinal fluid) dialysates were collected. The concentration of glutamate was measured by high-performance liquid chromatography with a fluorescence detector. The results showed that after chronic morphine administration, tolerance to antinociceptive effects of morphine was significantly greater in male rats (P<0.001). Sex differences in tolerance to morphine disappeared with gonadectomy of animals. There was also a significant sex difference in the glutamate level in the nucleus accumbens of morphine tolerant rats (P<0.001), ovariectomy of female rats decreased the glutamate level significantly (P<0.001), while gonadectomy did not change the glutamate level in males significantly. In conclusion, these experiments demonstrate that the excitatory amino acid release in the nucleus accumbens may be modulated by an estrogen-sensitive mechanism and play a role in the morphine analgesia and tolerance.

Analgesics, Opioid↗
PubMed2004

An antisense oligonucleotide to the N-methyl-D-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance.

We determined whether the i.t. administration of an 18-mer phosphodiester antisense oligodeoxynucleotide (ODN) that reduces the expression of the rat NMDAR1 subunit of the N-methyl-d-aspartate (NMDA) receptor would affect nociceptive behaviors and prevent the development of morphine tolerance. Rats received 5 microl of i.t. saline, 30 nM antisense, or mismatch ODN twice a day for 5 days (NMDA-induced nociception, NMDA-induced thermal hyperalgesia, NR1 mRNA, and ligand binding studies) or for 3 days (formalin study). For the tolerance study, 5 days of ODNs or saline were followed by 3 days of concurrent administration of ODNs or saline (twice a day) and i.t. morphine (three times a day). Antisense, but not mismatch, results in the reduction of formalin phase 2 flinching by 50%, the spinal cord dorsal horn levels of NMDAR1 mRNA by 30%, and ligand binding by 50%. The i.t. ED(50) for NMDA-induced nociceptive behaviors is doubled, and thermal hyperalgesia is blocked by antisense treatment. The effects of antisense on NMDA-induced nociception and thermal hyperalgesia are completely reversed by discontinuing antisense. The coadministration of antisense with increasing doses of i.t. morphine for 3 days attenuates the development of morphine tolerance. These results demonstrate that an in vivo antisense targeting of the NMDAR1 subunit results in antihyperalgesic effects and a partial blockade of spinal morphine tolerance. They provide additional support for the critical role of the NMDA receptor in these forms of spinal nociception and in the development of morphine tolerance and suggest the potential therapeutic utility of this approach.

Analgesics, Opioid↗
PubMed2000

Low frequency TENS is less effective than high frequency TENS at reducing inflammation-induced hyperalgesia in morphine-tolerant rats.

Both transcutaneous electrical nerve stimulation (TENS) and morphine are commonly used for relief of pain. Extensive research has been done on the effectiveness of each of these two methods for pain relief when given independently. However, very little literature exists examining the effectiveness of their combined use. Systemically administered morphine activates mu opioid receptors and when administered for prolonged periods results in analgesic tolerance. Low (4 Hz) and high (100 Hz) frequency TENS activate mu- and delta-opioid receptors, respectively, It is thus possible that TENS would be less effective in morphine-tolerant subjects. The current study investigated the effectiveness of high- and low-frequency TENS in the reversal of hyperalgesia in inflamed rats that were morphine-tolerant. Morphine tolerance was induced by subcutaneous implantation of morphine pellets over 10 days. Knee joint inflammation was induced by injection of kaolin and carrageenan into the knee joint cavity. Secondary heat hyperalgesia was tested by measuring the paw withdrawal latency to radiant heat (1) before pellet implantation (either morphine or placebo), (2) after pellet implantation and before inflammation, (3) after inflammation and (4) after TENS. Both high (100 Hz) and low (4 Hz) frequency TENS caused nearly 100% inhibition of secondary hyperalgesia in animals receiving placebo pellets. In contrast, the hyperalgesia in morphine-tolerant animals with knee joint inflammation was unaffected by low frequency TENS but fully reversed by high frequency TENS. These results suggest that patients who are tolerant to morphine may respond better to high frequency TENS than to low frequency TENS.

Animals↗
PubMed2006

Amitriptyline suppresses neuroinflammation and up-regulates glutamate transporters in morphine-tolerant rats.

The present study was performed to evaluate the effects of the tricyclic antidepressant amitriptyline on morphine tolerance in rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters with or without a microdialysis probe, then received a continuous i.t. infusion of saline (control) or morphine (15 microg/h) and/or amitriptyline (15 microg/h) for 5 days. The results showed that amitriptyline alone did not produce an antinociceptive effect, while morphine alone induced antinociceptive tolerance and down-regulation of spinal glutamate transporters (GLAST, GLT-1, and EAAC1) in the rat spinal cord dorsal horn. Co-administration of amitriptyline with morphine attenuated morphine tolerance and up-regulated GLAST and GLT-1 expression. On day 5, morphine challenge (10 microg/10 microl) resulted in a significant increase in levels of the excitatory amino acids (EAAs), aspartate and glutamate, in CSF dialysates in morphine-tolerant rats. Amitriptyline co-infusion not only markedly suppressed this morphine-evoked EAA release, but also preserved the antinociceptive effect of acute morphine challenge at the end of infusion. Glial cells activation and increased cytokine expression (TNFalpha, IL-1beta, and IL-6) in the rat spinal cord were induced by the 5-day morphine infusion and these neuroimmune responses were also prevented by amitriptyline co-infusion. These results show that amitriptyline not only attenuates morphine tolerance, but also preserves its antinociceptive effect. The mechanisms involved may include: (a) inhibition of pro-inflammatory cytokine expression, (b) prevention of glutamate transporter down-regulation, and even up-regulation of glial GTs GLAST and GLT-1 expression, with (c) attenuation of morphine-evoked EAA release following continuous long-term morphine infusion.

Amino Acid Transport System X-AG↗
PubMed1999

The role of nitric oxide in the development of morphine tolerance in rat hippocampal slices.

In the present study, we investigated the effects of a nitric oxide (NO) precursor, L-arginine, on the effect of different drugs, [trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e hydrochloride] (U-50,488, a kappa-opioid receptor agonist); dPTyr(Me)AVP (a vasopressin receptor antagonist); dizocilpine (MK-801, a N-methyl-D-aspartate (NMDA) receptor antagonist), to block the development of morphine tolerance or NO release in Sprague-Dawley rat hippocampal slices (450 microm). Slices were continuously superfused with artificial cerebrospinal fluid (ACSF) or drugs at 1 ml/min. Nichrome wire electrodes were placed in the Schaffer-collateral pathway and used to deliver biphasic 0.2-ms pulses of 5-30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes. The amount of NO released in the superfusate was measured as nitrite formation. When the slices were superfused with 10 microM morphine, the amplitude of population spikes increased 200%-300% in 30-40 min. However, this effect of morphine decreased, i.e., tolerance developed, after continuous superfusion of morphine for 2-6 h. On the other hand, the nitrite level was increased about 250% of the control level through 6 h of morphine superfusion. Co-superfusion of L-arginine with morphine could further increase the nitrite level and also facilitate the development of morphine tolerance. On the other hand, 3-Br-7-nitroindazole (a neuronal NO synthase inhibitor) decreased the nitrite level significantly and blocked the development of morphine tolerance. When either U-50,488 (200 nM) or dPTyr(Me)AVP (500 pM) or MK-801 (500 pM) was co-superfused with morphine (10 microM), the development of morphine tolerance was blocked significantly and the nitrite level decreased to 100%-150% of the control level. L-arginine (500 nM) significantly reversed the effect of these drugs to block the development of morphine tolerance or to decrease the nitrite level through 6 h of superfusion. These data suggest that NO may play a key role in the development of morphine tolerance. Drugs which suppress the synthesis or release of NO would be expected to block the development of morphine tolerance.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Inhibition of morphine tolerance and dependence by diazepam and its relation to cyclic AMP levels in discrete rat brain regions and spinal cord.

Diazepam inhibits morphine tolerance and dependence and reverses a decrease in the met-enkephalin level in brain induced by morphine. In this study, we investigated whether inhibition of morphine-induced tolerance and dependence by diazepam involved a change in cyclic AMP levels in discrete rat brain regions and spinal cord. Male Sprague-Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b. wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Tail-flick antinociception was measured 1 h after injections everyday. Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5), and the jumping behavior was observed for 30 min. Concomitant treatment with diazepam (0.25 mg/kg) significantly decreased the development of morphine tolerance and dependence. Diazepam (0.25 mg/kg) treated rats also showed a significant decrease in the jumping behavior compared to animals treated with morphine alone. Rats were sacrificed 2 h after the injection of saline or diazepam (0.25 mg/kg) on the fifth day. Cyclic AMP was estimated by RIA. In the control rats, the concentration of cyclic AMP in cortex was > hippocampus > cerebellum > hypothalamus > striatum > midbrain > pituitary > pons/medulla > spinal cord. There was no change in the concentration of cyclic AMP in any of the brain regions examined from morphine tolerant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Differentiation of spinal and supraspinal opioid receptors by morphine tolerance.

Mice treated for 72 hrs with morphine (subcutaneously implanted pellets) were tested with a variety of opioid receptor agonists to examine the development of tolerance and cross-tolerance to their analgesic action. The development of spinal and supraspinal tolerance following morphine treatment was evaluated by administering compounds systemically (sc), intrathecally (IT) and intracerebroventricularly (ICV). Following morphine treatment, tolerance to morphine analgesia was observed following IT, ICV and sc administration. Chronic morphine treatment also produced cross-tolerance to the analgesic effects of the selective delta opioid receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) following IT and ICV administration. However, morphine treatment selectively produced cross-tolerance to ICV [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAGO) (mu receptor agonist) analgesia, without altering IT DAGO analgesia. These results suggest that brain and spinal cord receptors mediating the effects of DAGO differ in terms of the development of cross-tolerance to morphine; and suggest that tolerance to systemic morphine may be due to changes in spinal delta and brain mu and delta receptor mechanisms.

Animals↗
PubMed1999

Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice.

Gene targeting was used to delete exon 2 of mouse DOR-1, which encodes the delta opioid receptor. Essentially all 3H-[D-Pen2,D-Pen5]enkephalin (3H-DPDPE) and 3H-[D-Ala2,D-Glu4]deltorphin (3H-deltorphin-2) binding is absent from mutant mice, demonstrating that DOR-1 encodes both delta1 and delta2 receptor subtypes. Homozygous mutant mice display markedly reduced spinal delta analgesia, but peptide delta agonists retain supraspinal analgesic potency that is only partially antagonized by naltrindole. Retained DPDPE analgesia is also demonstrated upon formalin testing, while the nonpeptide delta agonist BW373U69 exhibits enhanced activity in DOR-1 mutant mice. Together, these findings suggest the existence of a second delta-like analgesic system. Finally, DOR-1 mutant mice do not develop analgesic tolerance to morphine, genetically demonstrating a central role for DOR-1 in this process.

Analgesia↗
PubMed1999

Acquisition and expression of conditioned hypoalgesia in morphine-naive and morphine-tolerant rats.

The present study used a within-subject design to examine acquisition and expression of conditioned hypoalgesia in 50 male Wistar rats. Morphine-naive rats preexposed to a heat stressor with saline were hypoalgesic when subsequently tested for latencies to tail flick or paw lick. However, morphine-tolerant rats preexposed to the heat stressor with saline failed to display hypoalgesia when tested for latencies to tail flick, but showed hypoalgesia when tested for latencies to paw lick. Taken together, these findings suggest that expression of conditioned hypoalgesic responses in morphine-tolerant rats may depend on the nociceptive test used. Both morphine-naive and morphine-tolerant rats preexposed to the heat stressor with morphine failed to display hypoalgesia on either the tail-flick or the hot-plate test, demonstrating that morphine's ability to block acquisition of conditioned hypoalgesia is independent of the test used to assess nociceptive sensitivity.

Analgesics, Opioid↗
PubMed1989

Alpha 1-adrenoreceptor-mediated increase in acetylcholine release in brain slices during morphine tolerance.

Norepinephrine, clonidine, and phenylephrine increased the electrically evoked release of endogenous acetylcholine in cortical slices taken from morphine-tolerant guinea pigs. This effect was alpha 1-adrenoreceptor mediated and was opposite to the alpha 2-adrenoreceptor-mediated inhibition of acetylcholine release, normally elicited by norepinephrine and clonidine. In the presence of prazosin, clonidine recovered its normal inhibitory properties, suggesting that morphine tolerance induced the appearance of an alpha 1-adrenoreceptor-mediated response that overshadowed, but did not cancel, the still present alpha 2-adrenoreceptor inhibitory control. The attempt to prove the presence of alpha-adrenoreceptors on the nerve endings by testing the effect of norepinephrine in synaptosomal preparations (preloaded with [3H]choline and depolarized with KCl and veratridine) was unsuccessful. Therefore the problem of the exact location of this excitatory input remains to be solved. These results confirm previous findings reporting the increase in cortical acetylcholine release induced by the alpha-adrenoreceptor agonists in morphine-tolerant, freely moving guinea pigs and demonstrate that opiate tolerance inverts the direction of the noradrenergic modulation even in the isolated intracortical cholinergic structures.

Acetylcholine↗
PubMed1994

Dextromethorphan attenuates and reverses analgesic tolerance to morphine.

Tolerance to the antinociceptive (analgesic) effect of morphine, a mu-opioid agonist, was developed in male CD-1 mice as assessed by a shift to the right of the analgesic (tail-flick) dose-response curves and an increase in the ED50 values. Administration of dextromethorphan at 30 mg/kg s.c., but not saline, 30 min prior to an escalating 3 times per day (t.i.d.) morphine dosing schedule prevented a 5-fold increase in the morphine ED50 value observed on treatment day 4. Concurrent administration of dextromethorphan at 12 mg/kg/24 h by s.c. infusion prevented the 6-fold increase in the morphine ED50 value that was observed in control mice that received morphine at 30 mg/kg/24 h by s.c. infusion. Implantation of two 25 mg morphine pellets resulted in a 10-fold increase in the morphine ED50 value on treatment day 4. Administration of dextromethorphan at 30 mg/kg s.c. t.i.d., but not saline, resulted in a reversal of morphine tolerance with the almost complete return of the morphine ED50 value to the control (opioid naive) value. These results demonstrate that dextromethorphan, an NMDA receptor antagonist can modulate morphine (mu-receptor)-mediated tolerance.

Analgesics↗
PubMed2001

Inhibition of morphine tolerance and dependence by MS-153, a glutamate transporter activator.

We investigated the effects of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), which is reported to accelerate glutamate uptake, on the development of morphine tolerance and physical dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10-45 mg/kg, s.c.) for 5 days. First, co-administration of MS-153 (12.5 mg/kg, s.c.) did not affect the morphine's potency for its acute antinociceptive effect (1 and 3 mg/kg, s.c.). Next, co-administrations of MS-153 (1, 3 and 12.5 mg/kg, s.c.) during repeated morphine treatments significantly attenuated the development of tolerance to the antinociceptive effect of morphine (3 mg/kg, s.c.) and suppressed the naloxone (10 mg/kg, i.p.)-precipitated withdrawal signs (jumps and body weight loss). The inhibitory effect of MS-153 on the withdrawal signs was due to the attenuation of the development of dependence rather than that of expression of withdrawal signs. These results suggest that MS-153, a glutamate transporter activator, has an inhibitory effect on the development of morphine tolerance and physical dependence.

ATP-Binding Cassette Transporters↗