Development Of Cross-tolerance Research Articles

On the mechanism of cross-tolerance between morphine- and nicotine-induced antinociception: Involvement of calcium channels

The present study focused on the evaluation of a mechanism of nicotine-induced antinociception and cross-tolerance to antinociceptive effects between nicotine and morphine in mice. The results indicate that, at a dose of 3 mg/kg, nicotine produced a significant antinociception in the hot-plate test. Additionally, the L-type voltage-dependent calcium channel antagonists, nimodipine, verapamil and diltiazem (5, 10 and 20 mg/kg), as well as an opioid receptor antagonist naloxone (0.5 and 1 mg/kg), dose-dependently attenuated this nicotine-induced antinociception. In a second series of experiments, mice were treated with morphine (25 and 50 mg/kg) once daily, for 3 days. On the 4th day, the antinociceptive response of morphine (10 mg/kg) and nicotine (3 mg/kg) was measured. Tolerance to the effects of both drugs was observed only in mice pretreated with the highest dose of morphine. Furthermore, the administration of nimodipine, diltiazem, flunarizine (10 and 20 mg/kg), but not of verapamil (10 and 20 mg/kg) nor mecamylamine (1 and 2 mg/kg) prior to morphine injections, prevented this cross-tolerance to the antinociceptive effects of morphine and nicotine. These findings support the hypothesis that similar opioid- and calcium-dependent mechanisms are involved in morphine- and nicotine-induced antinociception and in the development of cross-tolerance between these drugs.

Sensitivity to the effects of opioids in rats with free access to exercise wheels: mu-opioid tolerance and physical dependence.

Exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e. pain) thresholds in both human and animal subjects. During chronic, long-term exercise, sensitivity to the effects of morphine and other mu opioids decreases, leading some investigators to propose that exercise may lead to the development of cross tolerance to exogenously administered opioid agonists. The purpose of the present investigation was to examine the effects of chronic exercise on sensitivity to mu opioids, and to determine whether these effects can be attributed to the development of opioid tolerance and dependence. Rats were obtained at weaning and housed singly in standard polycarbonate cages (sedentary) or modified cages equipped with exercise wheels (exercise). After 6 weeks under these conditions, opioids possessing a range of relative efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine) were examined in a warm-water tail-withdrawal procedure. Morphine, levorphanol and buprenorphine produced maximal levels of antinociception in both groups of rats, but all were more potent in sedentary rats than in exercising rats. Butorphanol and nalbuphine produced maximal levels of antinociception in sedentary rats under some conditions in which they failed to produce antinociception in exercising rats. Sensitivity to the effects of buprenorphine was decreased in sedentary rats that were transferred to cages equipped with exercise wheels, and increased in exercising rats that were transferred to sedentary housing conditions. In the latter group, exercise output prior to housing reassignment was positively correlated with increases in sensitivity to buprenorphine following housing reassignment. Naloxone administration precipitated a mild withdrawal syndrome in exercising rats that was not readily apparent in sedentary rats. These data suggest that chronic exercise leads to the development of mu-opioid tolerance and physical dependence, and that these effects are similar to those produced by chronic opioid administration.

Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance: distinct alterations in IL-1 receptor-associated kinase.

Human Toll-like receptor (TLR) 4 and TLR2 receptors recognize LPS or lipoteichoic acid (LTA), respectively. Prolonged exposure of human macrophages/monocytes to bacterial LPS induces a state of adaptation/tolerance to subsequent LPS challenge. Inflammatory gene expressions such as IL-1beta and TNF-alpha are selectively repressed, while certain anti-inflammatory genes such as secretory IL-1R antagonist are still induced in LPS-adapted/tolerant cells. In this report, we demonstrate that LPS-tolerized human promonocytic THP-1 cells develop cross-tolerance and no longer respond to LTA-induced IL-1beta/TNF-alpha production, indicating that disruption of common intracellular signaling is responsible for the decreased IL-1beta/TNF-alpha production. We observe that down-regulation of IL-1R-associated kinase (IRAK) protein level and kinase activity closely correlates with the development of cross-tolerance. IRAK protein levels and kinase activities in LPS-tolerized cells remain low and hyporesponsive to subsequent LPS or LTA challenges. We also demonstrate that THP-1 cells with prolonged LTA treatment develop LTA tolerance and do not express IL-1beta/TNF-alpha upon further LTA challenge. Strikingly, cells tolerized with LTA are only refractory to subsequent LTA challenge and can still respond to LPS stimulation. Correspondingly, stimulation of TLR2 by LTA, although activating IRAK, does not cause IRAK degradation. IRAK from LTA-tolerized cells can be subsequently activated and degraded by further LPS challenge, but not LTA treatment. Our studies reveal that LTA-induced tolerance is distinct compared with that of LPS tolerance, and is likely due to disruption of unique TLR2 signaling components upstream of MyD88/IRAK.

Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies.

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted due to the development of nitrate tolerance. With initiation of nitroglycerin therapy one can detect neurohormonal activation and signs for intravascular volume expansion. These so called pseudotolerance mechanisms may compromise nitroglycerin's vasodilatory effects. Long-term treatment with nitroglycerin is also associated with a decreased responsiveness of the vasculature to nitroglycerin's vasorelaxant potency suggesting changes in intrinsic mechanisms of the tolerant vasculature itself may also contribute to tolerance. More recent experimental work defined new mechanisms of tolerance such as increased vascular superoxide production and increased sensitivity to vasoconstrictors secondary to an activation of the intracellular second messenger protein kinase C. As potential superoxide producing enzymes, the NADPH oxidase and the nitric oxide synthase have been identified. Nitroglycerin-induced stimulation of oxygen-derived free radicals together with NO derived from nitroglycerin may lead to the formation of peroxynitrite, which may be responsible for the development of tolerance as well as for the development of cross tolerance to endothelium-dependent vasodilators. The oxidative stress concept of tolerance and cross tolerance may explain why radical scavengers such as vitamin C or substances which reduce oxidative stress, such as ACE-inhibitors, AT1 receptor blockers or folic acid, are able to beneficially influence both tolerance and nitroglycerin-induced endothelial dysfunction. New aspects concerning the role of oxidative stress in nitrate tolerance and nitrate induced endothelial dysfunction and the consequences for the NO/cyclicGMP downstream target, the cGMP-dependent protein kinase will be discussed.

Heat acclimation: phenotypic plasticity and cues to the underlying molecular mechanisms

Acclimation, in contrast to evolutionary adaptation, is a “within life time phenotypic adaptation” resulting in a widening of the dynamic regulatory range of body temperature. Increased efficiency and capacity of the thermoregulatory effectors, and delayed onset of the temperature threshold for thermal injury, contribute to the beneficial effects of acclimation. Reprogrammed gene expression and changes in cellular signaling underlie these responses. Constitutive elevation of the inducible heat shock protein (HSP) 72 kDa provides cytoprotection and delays thermal injury without the need for de novo HSP synthesis upon thermal stress. The time window for evocation of heat acclimation is the early phase of acclimation, the short-term heat acclimation (STHA), with accelerated sympathetic excitability and a drop in plasma thyroxin playing an essential role. An important consequence of thermal acclimation is the development of cross-tolerance between heat acclimation and ischemia/reperfusion insults. The beneficial implications of this feature are discussed.

Lack of Crosstolerance Between Morphine and Morphine-6-glucuronide as Revealed by Locomotor Activity

Morphine-6β-glucuronide is a major metabolite of morphine. We wanted to examine whether the effects related to opiate CNS stimulation could be mediated by different receptors for morphine and M6G by studying the development of crosstolerance between these two drugs. The effect studied was locomotor activity in C57BL/6JBom mice. We observed a dose-dependent development of tolerance to daily injections of morphine, with 20 μmol/kg giving the most rapid development of tolerance, apparent already on the second day of treatment. This was also observed for the same dose of M6G. Crosstolerance to M6G was measured both after 1 day pretreatment and 7 days pretreatment with morphine 20 μmol/kg, while the crosstolerance to morphine was tested only after 1 day pretreatment with M6G (20 μmol/kg). Lack of crosstolerance towards M6G after 1 day of morphine pretreatment was observed, whereas crosstolerance to M6G was observed after 7 days of exposure to morphine pretreatment. Crosstolerance after M6G pretreatment to morphine was observed. It was concluded that the main part of the effect caused by M6G was mediated through a specific M6G receptor.

Mechanism of the antialcohol effect of gamma-hydroxybutyric acid

Treatment with gamma-hydroxybutyric acid has been reported to effectively decrease alcohol craving and consumption as well as alcohol withdrawal symptoms in alcoholics. We describe the results of animal studies demonstrating the ability of gamma-hydroxybutyric acid to reduce (1) the severity of ethanol withdrawal signs in rats rendered physically dependent on ethanol and (2) voluntary ethanol intake in selectively bred Sardinian alcohol-preferring rats. Furthermore, we review experimental data suggesting that gamma-hydroxybutyric acid and ethanol have several pharmacological effects in common. Relevant similarities are: (1) stimulation of firing rate of dopaminergic neurons and dopamine release in specific rat brain areas; (2) development of cross-tolerance to the motor-impairing effects after repeated administration in rats; 3) abuse potential, as indicated by self-administration of pharmacologically relevant doses of gamma-hydroxybutyric acid in rats and mice; (4) induction of anxiolytic effects in rats; and (5) induction of similar discriminative stimulus effects, as evidenced by symmetrical generalization in a drug discrimination study in rats. These lines of evidence are discussed in relation to gamma-hydroxybutyric acid exerting its antialcohol effects by a substitution mechanism.

The development of cross-tolerance between morphine and nicotine in mice

In the present study, cross-tolerance between nicotine and morphine in mice has been investigated. Mice were treated subcutaneously with three doses of morphine (12.5, 25 and 50 mg/kg) once daily, for 3 days in order to produce tolerance to morphine and nicotine antinociception. Tolerance only developed in the high dose group. On the 4th day, the antinociceptive effect of three test doses of morphine (3, 6 and 9 mg/kg) or nicotine (0.01, 0.05 and 0.1 mg/kg) were assessed. Tolerance to the responses of both drugs were observed. Intraperitoneal administration of nicotine (2 mg/kg) three times a day for a period of 12 days, also induced tolerance to the antinociceptive effects of both morphine and nicotine. When animals were tested on the 13th day, the antinociceptive responses of morphine or nicotine were reduced. Another group of animals was treated with low doses of morphine daily (12.5 or 25 mg/kg) plus nicotine (2 mg/kg) three times daily for 3 days. In this group of animals, the antinociception to either morphine or nicotine was tested. Combination of both drugs caused an increase in tolerance to either drug. It is concluded that there is cross-tolerance between the two drugs.

The rate-decreasing effects of fentanyl derivatives in pigeons before, during and after chronic morphine treatment.

Mirfentanil is a fentanyl derivative with non-opioid actions, including non-opioid antinociceptive effects in rhesus monkeys. The current study examined the rate-altering effects of mirfentanil and several other compounds in pigeons to assess: 1) the opioid and non-opioid actions of acutely-administered fentanyl derivatives; and 2) the development of cross-tolerance between each of these compounds and morphine. Seven pigeons responded under a fixed-ratio 20 (FR20) schedule of food delivery. In untreated pigeons, fentanyl, morphine, naltrexone, ketamine and three fentanyl derivatives (mirfentanil, OHM3463 and OHM3295) decreased rates of key pecking in a dose-related manner. Naltrexone (0.1-1.0 mg/kg) attenuated the effects of OHM3463 and not mirfentanil or OHM3295, suggesting non-opioid mediation of the rate-decreasing effects for the latter two fentanyl derivatives. Subjects were treated daily with morphine for 9 weeks, up to a dose of 100 mg/kg per day, during which time the dose-effect curves for morphine, fentanyl and OHM3463 shifted rightward 6-, 10- and 2-fold, respectively, indicating the development of tolerance to morphine and cross-tolerance to fentanyl and OHM3463. Dose-effect curves for ketamine, OHM3295 and mirfentanil were not shifted to the right during morphine treatment, and the dose-effect curve for naltrexone was shifted leftward 180-fold. To the extent that rate-decreasing effects are predictive of antinociceptive effects, these data suggest that some fentanyl derivatives might be useful therapeutics under conditions where tolerance develops to morphine-like opioids.

Cross tolerance to environmental stress and endotoxin

Mild DIC-like phenomena develop in rodents exposed to environmental stress, induced by prolonged fluctuation in ambient temperature, known as SART (specific alternation of rhythm in temperature) stress, the symptoms being essentially similar to those produced by endotoxin. The aim of the present study was to investigate whether common mechanisms are involved in the stress-induced DIC-like phenomena and endotoxaemia. The mortality in mice after intraperitoneal injection with endotoxin at 8.3, 16.7 and 33.3 mg kg increased in a dose-dependent manner. In the mice exposed to stress for 7 days, the death rate following endotoxin at 8.3 mg kg was markedly lower than that in unstressed mice, although no difference was detected between the two groups following endotoxin at 16.7 and 33.3 mg kg . Conversely, repeated administration of endotoxin at a low dose, 0.5 mg kg , during exposure to stress for 7 days inhibited the stress-induced thrombocytopenia and hypofibrinogenemia. These findings indicate the development of cross tolerance to prolonged environmental stress and endotoxin, implying involvement of a common mechanism.

Antagonism of convulsions but failure to enhance GABA(A) receptor function by felbamate in mice tolerant to diazepam.

The transfer of tolerance between drugs may indicate a common mode of action. The development of cross-tolerance to the anticonvulsant effect of felbamate after long-term treatment of mice with diazepam, a positive modulator of gamma-aminobutyric acid (GABA)-mediated transmission, was therefore studied in order to clarify the mechanism of this action of felbamate. A challenge injection of felbamate, administered 36 h after the last dose of chronic diazepam treatment, antagonized convulsions elicited by administration of isoniazid. In contrast, felbamate had no effect on the isoniazid-induced increase in t-[35S]butylbicyclophosphorothionate binding to cerebral cortical membranes of diazepam-tolerant mice. These results suggest that the action of felbamate on GABAergic transmission is not required for the anticonvulsant effect of this drug. This conclusion is consistent with studies that have indicated that the antiepileptic activity of felbamate depends on its modulatory activity at excitatory amino acid receptors.

Relationship of lead-induced proteins to stress response proteins in astroglial cells.

Astroglial cells are resistant to cell death and morphologic damage following lead (Pb) exposure at concentrations which elicit detrimental effects in neurons. A possible explanation may be that astroglial cells respond to Pb by increasing the expression of specific proteins, such as heat-shock proteins (HSPs), which confer resistance to low levels of Pb. However, there has been relatively limited information regarding the ability of Pb to evoke the synthesis of HSPs. In the current study, pulse-labeling of cultured astroglial proteins with [3H]-leucine was used to evaluate the nature of Pb-induced changes in protein expression. The effect of Pb on newly synthesized proteins was compared to the response elicited by heat-shock and oxidative injury. Immunoblot analysis was utilized to examine alterations in levels of various stress proteins including HSP27, HSP70, HSP90, and heme oxygenase-1 (HO-1). Even though Pb induced the synthesis of proteins with estimated molecular weights of 23 kDa, 32 kDa, 70 kDa, and 90 kDa, the accumulation of HSPs other than HO-1 was not observed. Hyperthermia and treatment with Na arsenite both resulted in enhanced expression of HSP70 and HO-1. In addition, exposure to hydrogen peroxide (H2O2), cadmium (Cd), and lipopolysaccharide (LPS) stimulated a rise in HO-1 levels. Although cellular insult failed to elicit an increase in either HSP27 or HSP90, cultured astroglia expressed readily detectable levels of both these proteins. Furthermore, Pb exposure resulted in the development of crosstolerance to subsequent injury by treatment with either Cd or H2O2. The results of this study indicate that Pb triggers a less conventional stress response in astroglial cells, which may provide enhanced resistance to the toxic effects of Pb.

Oxytocin blocks the development of heroin-fentanyl cross-tolerance in mice

The development of cross-tolerance to an analgesic effect was observed between two μ-receptor agonists, heroin and fentanyl. Repeated treatments with heroin twice a day for 4 days resulted in a decreased nociceptive effect to fentanyl on day 5. The fentanyl dose-response line shifted to the right, and was considered to be a sign of the development of cross-tolerance. Peripheral treatment with oxytocin did not block the development of heroin-fentanyl cross-tolerance. However, intracerebroventricular administration of oxytocin blocked the development of tolerance, causing a leftward shift in the dose-response curve and supporting the assumption that oxytocin blocks the development of heroin-fentanyl cross-tolerance via CNS mechanisms.

Crosstolerance between butorphanol and morphine in rats

To investigate the antinociceptive effects of morphine and U-50,488 after continuous administration with butorphanol, rats were intracerebroventricularly (ICV) infused with butorphanol (26 nmol/μl/h) through osmotic minipumps for 3 days. Six hours after termination of infusion, the rats were challenged with different doses of morphine or U-50,488. Antinociceptive effects, as assessed by tail-flick and acetic acid writhing tests, were measured 15 min after challenge. Development of crosstolerance to morphine was evident in butorphanol-infused animals. The study also revealed that crosstolerance to butorphanol developed in continuously ICV morphine-infused animals. Continuous ICV infusion with butorphanol produced a marked rightward shift of the antinociceptive dose-response curve resulting from U-50,488 challenge. These results showed that there is an antinociceptive crosstolerance between butorphanol and morphine, and crosstolerance to U-50,488 developed in continuously butorphanol-infused animals. The present data suggested that chronic ICV treatment with high doses of butorphanol can lead to desensitization of the antinociceptive systems mediated through the central κ as well as μ receptors in rats.

O-398 - Changes in N-type calcuim channels following the development of cross-tolerance between morphine and clonidine.

O-398 - Changes in N-type calcuim channels following the development of cross-tolerance between morphine and clonidine.

Effect of prolonged administration of clonidine on [ 3H]PN 200-110 and [ 125I]ϵ-conotoxin binding in mouse brain

The effect of chronic exposure to clonidine or morphine on clonidine- and morphine-induced analgesia in mice was examined. Binding of L- or N-type calcium channel antagonist to cortical membrane fractions was also compared between these groups of mice. A decrease in the analgesic effect of clonidine and morphine was observed following prolonged administration of clonidine or morphine. Binding of [ 3H]PN 200-110, an L-type calcium channel antagonist, decreased following prolonged administration of clonidine whereas it increased after morphine treatment. On the other hand, a significant increase of [ 125I]ϵ-conotoxin, an N-type calcium channel antagonist, binding was observed after chronic clonidine or morphine treatment. These results will be discussed in relation with the possible development of cross-tolerance between clonidine and morphine through the change in calcium channels, more specifically in N-type channels.

Tolerance to adenosine's accentuation of ethanol-induced motor incoordination in ethanol-tolerant mice.

Our previously published reports have provided data that have supported a functional correlation between ethanol-induced changes in the characteristics of adenosine receptor, adenosine uptake and release in the brain, and ethanol-induced motor incoordination. The present data demonstrated a cross-tolerance between ethanol and adenosine further supporting the hypothesis that brain adenosine modulates the motor impairing effects of ethanol. Mice that received (-)-N6-cyclohexyladenosine (CHA) [0.25 mg/kg/day, intraperitoneally (ip)] for 10 days exhibited marked attenuation (cross-tolerance) to acute ethanol-induced motor incoordination compared with chronic saline (ip) controls. The attenuation of acute ethanol-induced motor incoordination was essentially same in animals that received CHA (25 ng/5 microliters/day for 10 days) by the intracerebroventricular (icv) route as opposed to the controls that chronically received artificial cerebral spinal fluid by the same route. Similarly, tolerance was exhibited to acute CHA (0.125 mg/kg ip and 12.5 ng/5 microliters icv) by animals fed liquid ethanol (19.5 g/kg/24 hr) for 10 days compared with none in the pair-fed sucrose controls. Scatchard plots using cerebellar tissue homogenates from animals given chronic CHA or chronic ethanol indicated no change in Bmax and/or Kd values for CHA binding when compared with CHA binding in tissues from their respective controls. However, a lack of any change in the binding characteristics cannot rule out the involvement of adenosine receptors in the observed cross-tolerance between ethanol and CHA. The results may suggest desensitization of adenosine A1 receptors due to chronic CHA and ethanol as an alternate possible explanation in the development of cross-tolerance between adenosine (CHA) and ethanol.

Oxytocin blocks the development of heroin-enkephalin cross-tolerance in mice

The development of cross-tolerance to an analgesic effect has been observed between a μ-receptor agonist, heroin, and a δ-receptor agonist, Met 2-Pro 5-enkephalinamide. Repeated treatments with heroin twice a day for 4 days resulted in a decreased nociceptive effect to enkephalin on day 5. The enkephalin dose-response line was shifted to the right, considered a sign of the development of cross-tolerance. Peripheral treatment with oxytocin blocked the development of heroin-enkephalin cross-tolerance. A similar effect was observed after intracerebroventricular administration oxytocin, supportinng our assumption that oxytocin blocks the development of heroin-enkephalin cross-tolerance via CNS mechanisms.

Genetic differences in heat-induced tolerance to cadmium in cultured mouse embryos are not correlated with changes in a 68-kD heat shock protein.

Heat-induced cross-tolerance to cadmium was investigated in two inbred strains of mice, BALB/c and SWV, using a whole embryo culture system. Embryos were exposed to a pretreatment of 5 min at 43 degrees C and subsequently to an embryotoxic concentration of cadmium, 1.75 microM. The two types of embryos responded differently to the heat pretreatment, as cross-tolerance was induced in SWV but not in BALB/c mice. In SWV embryos, prior exposure to 43 degrees C for 5 min essentially eliminated the negative effects of cadmium on embryonic development and growth. However, in BALB/c embryos, no protection was observed. The variation in development of cross-tolerance in embryos from the two strains of mice was not correlated with differences in the induction of a 68-kD heat-shock protein (hsp68). There was a rapid increase in this protein in both strains after the initial heat exposure but not excess induction in the SWV strain that developed tolerance. The induction of hsp68 is therefore not sufficient to elicit cross-tolerance, and other mechanisms are likely to be important in the protective response of the embryo.

Role of sodium cromoglycate on analgesia, locomotor activity and opiate withdrawal in mice.

The role of sodium cromoglycate (CRO) on analgesia, locomotor activity and morphine withdrawal in mice was studied in morphine-dependent and drug-naive mice. CRO (0.5, 1, 5, 10, 30, 50 and 100 mg/kg, SC) induces analgesia (hot plate), an effect blocked by previous administration of the opiate antagonist naloxone (1 mg/kg). Furthermore, CRO (30 mg/kg) potentiates morphine analgesia. In morphine-tolerant mice, moderate doses of CRO (0.5, 1, 5, 10 and 30 mg/kg) do not induce analgesia, which suggested the development of cross tolerance between CRO and morphine, whereas coadministration of CRO and morphine in morphine tolerant animals restored the sensitivity to morphine. Administration of CRO (10 and 30 mg/kg) induces an increase in spontaneous locomotor activity, and previous administration of naloxone (1 mg/kg) blocks this effect, whereas CRO (10 mg/kg) blocks morphine (10 mg/kg) and amphetamine (3 mg/kg)-induced hyperactivity. CRO (10, 50 and 100 mg/kg) induces a significant and dose-dependent reduction in the number of jumps ("jumping up") during naloxone (1 mg/kg)-induced withdrawal in morphine-dependent mice. Finally, CRO (100 mg/kg) reduces the "wet dog shake" phenomenom during naloxone-induced withdrawal in morphine-dependent mice. These results suggest a possible stabilizing effect of CRO on the membranes of neurones that mediate analgesia, locomotor activity and opiate abstinence. Changes and inhibition of DA, NA and 5-HT release may also explain these effects.