Rapid Development Of Tolerance Research Articles

Pharmacokinetic/Pharmacodynamic Modelling of Venlafaxine

Venlafaxine and its major active metabolite O-desmethylvenlafaxine selectively inhibit serotonin and norepinephrine reuptake from the synaptic gap. The inhibition of norepinephrine uptake is assumed to enhance antidepressant efficacy when venlafaxine is given at higher therapeutic doses. Thus investigation of the concentration-response relationship of noradrenergic effects is of clinical interest. We used pupillography as a test system for the pharmacodynamic response to venlafaxine, since it had been shown to be useful for assessment of noradrenergic effects on the autonomous nervous system. The aim of the study was to develop a pharmacokinetic/pharmacodynamic model by means of nonlinear mixed-effects modelling in order to describe the time course of the noradrenergic response to venlafaxine. Twelve healthy male subjects received venlafaxine 37.5 mg or placebo orally twice daily for 7 days and subsequently 75 mg or placebo twice daily for another 7 days. After a 14-day washout phase, the two groups were crossed over. After the last dose of venlafaxine or placebo on day 14, blood samples were drawn to determine venlafaxine and O-desmethylvenlafaxine concentrations and the amplitude and recovery time of the pupillary light reflex were measured. A pharmacokinetic/pharmacodynamic model was developed to describe the data using nonlinear mixed-effects modelling. The pharmacokinetic part of the model could be simultaneously fitted to both venlafaxine and O-desmethylvenlafaxine data, yielding precise parameter estimates that were similar to published data. The model detected high variability of the intrinsic clearance of venlafaxine (94.8%), most likely due to cytochrome P450 2D6 polymorphism. Rapid development of tolerance of the pupillary light reflex parameters was seen and could be successfully accounted for in the pharmacodynamic part of the model. The half-life of development and regression of tolerance was estimated to be 30 minutes for the amplitude and 40 minutes for the recovery time. The time course of the effect and the concentration-response relationship were successfully described by a pharmacokinetic/pharmacodynamic model that takes into account the rapid development of tolerance of pupillary light reflex parameters. This provides a basis for further investigations of the applicability of pupillography as a surrogate measurement of the effectivity of antidepressant drugs with norepinephrine reuptake-inhibiting properties.

Influence of epipregnanolone on the modulation of rapid tolerance to ethanol by neurosteroids

The objective of the present study was to investigate the effect of epipregnanolone on the influence of neurosteroids on the development of rapid tolerance to the motor impairing and hypothermic effects of ethanol. Experiment 1: on Day 1 groups of mice were pretreated with saline or with epipregnanolone. After 30 min each group was further divided in subgroups that received ethanol or saline. Thirty, 60 and 90 min after the injections the animals were tested on the rota-rod or the body temperature was measured. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. Experiment 2 and 3: On Day 1 groups of mice were treated with epipregnanolone and after 15 min each group was divided into three groups in order to receive pregnenolone sulfate, dehydroepiandrosterone sulfate or saline. Thirty minutes later, each group was further divided into two subgroups in order to receive ethanol or saline, respectively, and 30, 60 and 90 min later the animals were tested as in the experiment 1. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. Pretreatment with epipregnanolone (0.10-0.30 mg/kg) significantly blocked the development of tolerance to the motor impairing and hypothermic effects induced by ethanol in mice. Considering tolerance to ethanol-induced motor impairment, epipregnanolone (0.15 mg/kg) reversed the stimulatory action of dehydroepiandrosterone sulfate (0.15 mg/kg), but did not affect the actions of pregnenolone sulfate (0.08 mg/kg). Moreover, epipregnanolone prevented the inhibitory action of allotetrahydrodeoxycorticosterone (0.10 mg/kg). In relation to ethanol-induced hypothermia, the results showed that pretreatment with epipregnanolone (0.30 mg/kg) significantly prevented the stimulatory action of dehydroepiandrosterone sulfate and pregnenolone sulfate, as well as the inhibitory action of allotetrahydrodeoxicorticosterone (0.20 mg/kg), on tolerance to this effect. The results suggest a differential interaction between neurosteroids that might modulate the development of rapid tolerance to ethanol.

Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

To assess whether, using the current regulatory criteria, therapeutically important differences can exist between bioequivalent carbamazepine (CBZ) tablets. A secondary goal was to demonstrate quantitatively the relationship between the risk of neurological adverse effects to orally ingested CBZ and the rate of absorption. Results of a bioequivalence study by Olling et al. (Biopharm Drug Dispos 1999; 20: 19-28) were reanalysed. Following an exploratory data analysis step, a mixed-effect pharmacokinetic-pharmacodynamic (PK-PD) model was built to describe the dependence of adverse events on the CBZ concentration. Rapid development of tolerance was demonstrated for most neurological adverse effects, with a characteristic half-life of 02.29 h and an initial EC50 of 2.33 mg l(-1). The resulting tolerance PK-PD model was characterized further using the tools and terminology of sensitivity analysis. It was demonstrated that the maximum concentration (C(max)) exhibits poor PK and PD sensitivities, and that clinically significant differences can exist between formulations which otherwise comply with the bioequivalence requirements. In contrast, another PK metric, the partial AUC, was a much better marker of the early neurological adverse events observable during the absorption phase of the drug. In clinical and regulatory considerations, the development of acute tolerance for adverse effects of CBZ must be taken into account. Partial AUC reflects more sensitively the risk of adverse events than C(max). Instead of the current trend of tightening of the bioequivalence criteria for narrow therapeutic index drugs, the use of alternative, more sensitive PK metrics is proposed.

Activity-induced anorexia in rats augments the development of tolerance to morphine.

Restricting food intake (FI) to 1 h/day for rats housed in running wheels can serve as a model for the excessive exercise often observed in individuals with anorexia nervosa. When maintained on this schedule for several days, rats decrease food intake, increase running and can die of starvation. Studies have shown that freely fed rats allowed to run for 3 weeks become tolerant to morphine's pain-relieving actions. To determine if restricting FI in active rats would produce more rapid development of tolerance, active rats were fed for 24 or 1.5 h/day. When active food-restricted rats reached 75% of their free-feeding body weight, testing for morphine-induced antinociception (MIA) began. Ad lib-fed active rats, were tested for MIA after 3 weeks, or after the amount of time taken for food-restricted active rats to reach their target weight. Inactive rats were given ad lib food or pair-fed the amount of food consumed by active food-restricted rats, and tested for MIA after 3 weeks (ad lib fed) or 6 days (pair-fed). Food-restricted active rats increased running, decreased FI and by day 6, reached 75% of their free-feeding weight and were less sensitive to morphine's pain-relieving actions than rats in any of the inactive groups or active rats given free access to food and tested at the same time as the food-restricted rats. Increasing activity in food-restricted individuals may augment stimulation of endogenous opioid peptides, and thus accentuate the development of tolerance to opiate drugs.

Effects of SR141716 and WIN 55,212-2 on tolerance to ethanol in rats using the acute and rapid procedures

Our previous findings have shown rapid cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol and that intraperitoneal (i.p.) injection of cannabinoid receptor type 1 (CB1R) antagonist SR141716 (SR) does not interfere with tolerance to either of these drugs in mice. This study investigates the effects of SR, alone or in combination with the CB receptor agonist WIN 55,212-2 (WIN), on the development of acute and rapid tolerance to the incoordinating effect of ethanol in rats. Male Wistar rats received SR, through i.p. (0.5-2.0 mg/kg) or intracerebroventricular (i.c.v.) injections (0.5-4.0 microg), alone or together with WIN (1.0 microg, i.c.v.), in combination with ethanol (2.7 g/kg, i.p.). Another group received WIN (1.0 microg, i.c.v.) in combination with ethanol (2.3 g/kg), and the rats were tested for motor coordination. Rapid tolerance was assessed 24 h later by administering ethanol to all animals and retesting them under the same dose regimen. Acute tolerance was evaluated for 75 min after ethanol (3.0 g/kg, i.p.) in animals treated with SR or WIN (i.c.v.). The reduced motor impairment on day 2 (i.e., rapid tolerance) was blocked by SR (i.p. and i.c.v.). WIN (1.0 microg, i.c.v.) facilitated rapid tolerance and also prevented the blockade of rapid tolerance by SR (1.0 microg, i.c.v.). In the acute tolerance procedure, SR did not affect the motor incoordination induced by ethanol. The results suggest that the endocannabinoid system may contribute to the development of rapid tolerance to ethanol.

DrosophilaHomer Is Required in a Small Set of Neurons Including the Ellipsoid Body for Normal Ethanol Sensitivity and Tolerance

The molecular mechanisms occurring in the nervous system that underlie behavioral responses to ethanol remain poorly understood. Here, we report that molecular requirements for two of these responses, initial sensitivity and the development of rapid tolerance, comap to the same small set of neurons. We show that null homer mutant flies exhibit both increased sensitivity to the sedative effects of ethanol and failure to develop normal levels of rapid tolerance. Both the sensitivity and rapid tolerance phenotypes of the homer mutants are rescued by the expression of wild-type homer in a subset of neurons that include the ellipsoid body. Thus, some of the molecular- and systems-level requirements for these two behavioral responses to ethanol are identical.

The frequency of interictal activity was modulated by the generation of the activity per se

Gaboxadol, a selective extra synaptic GABAA receptor agonist, has been in clinical development for the treatment of insomnia. Development of tolerance to therapeutic effects (e.g. hypnotic and anticonvulsant and sedative) and withdrawal symptoms (e.g. REM sleep rebound and reduced seizure threshold) upon treatment discontinuation is reported for GABAA receptor allosteric modulators acting via the benzodiazepine binding site, e.g. zolpidem and indiplon. We conducted a head to head comparison in rats of the hypnotic (sleep EEG after 21 daily doses and 24 and 48 h after the last dose) and seizure threshold modifying (bicuculline assay 24 h after 28 daily doses) effects of gaboxadol and benzodiazepine ligands. Furthermore, we investigated in further details a previously reported apparent rapid development of tolerance to gaboxadol's effects in a rat rotarod motor coordination assay and related this effect to CNS exposure levels and in vitro potency at extra synaptic GABAA receptors.Sleep EEG studies demonstrated lack of tolerance and withdrawal effects after 28 daily doses with gaboxadol, whereas zolpidem produced both tolerance and withdrawal effects under a similar dosing regimen. Daily dosing with gaboxadol, zolpidem or indiplon for 28 days and acute discontinuation of treatment left the threshold to bicuculline-induced seizures unchanged. The rapidly attenuated effect of repeated gaboxadol dosing was confirmed in the rotarod model. However, re-challenge of gaboxadol insensitive animals with gaboxadol produced a maximum response, ruling out that receptor desensitisation accounts for these effects. By comparing CNS exposure at rotarod responses and concentration response relation at cloned GABAA receptors expressed in Xenopus oocytes it appears that the decline in response in the rotarod model coincides with the steep part of the concentration response curve for gaboxadol at extra synaptic GABAA receptors.In conclusion, rat sleep EEG repeated dose studies of gaboxadol confirm a hypnotic-like profile and no withdrawal effects, whereas tolerance and withdrawal effects were shown with zolpidem. Withdrawal from gaboxadol, zolpidem and indiplon did not affect the seizure threshold to bicuculline. Gaboxadol's apparent rapid development of tolerance in the rotarod assay appears to be kinetically determined.

Novel Approaches to Pain Relief Using Venom-Derived Peptides

More than one and a half billion people worldwide suffer from moderate to severe chronic pain, the National Institute of Health estimates that pain costs health services approximately 100 billion US Dollar annually. Existing drugs for the treatment of pain are often associated with serious side effects and rapid development of tolerance, thus, there is a need for new, more selective, molecules. Ion channels play an important role throughout the pain response, from nociception via transient receptor potential (TRP) channels or ATP-sensitive receptors, propagation of action potentials by voltage-sensitive sodium and potassium channels to control of the release of neurotransmitters from presynaptic terminals of dorsal root ganglion (DRG) neurones in the dorsal horn by voltage-gated calcium channels. Venoms are complex mixtures of bioactive molecules that have evolved for prey capture and defence, many of these molecules have a high selectivity for physiological processes, including modulation of ion channel function, which has not been matched by man made molecules. Thus, venoms represent an extensive source of molecules for the development of therapeutic agents. This report will review the key ion channel targets for pain relief, and venom-derived molecules and their analogues acting at these targets. We will concentrate particularly on peptides isolated from Conus venom as these represent one of the best-characterised toxin families. Our current knowledge of the molecular pharmacology of these toxin molecules will be reviewed and problems associated with using peptides as therapeutics will be discussed, along with strategies to overcome these.

Comparison of Pharmacokinetics and Vasodilatory Effect of Nebulized and Infused Iloprost in Experimental Pulmonary Hypertension: Rapid Tolerance Development

Aerosolized iloprost has been suggested for selective pulmonary vasodilatation in severe pulmonary hypertension, but its pharmacokinetic profile is largely unknown. In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was employed for establishing stable pulmonary hypertension. Delivery of a total amount of 75, 300, and 900 ng of iloprost to the bronchoalveolar space by a 10 min-aerosolization maneuver caused a dose-dependent pulmonary vasodilatation. Similarly, dose-dependent appearance of iloprost in the recirculating perfusate was noted, with maximum intravascular concentrations of iloprost ranging at 140, 510, and 1163 pg/mL at the same time period. Comparing pharmacokinetics and pharmacodynamics in a more detailed fashion, the following aspects were of interest. (i) The bioavailability (i.e., the percentage of aerosolized iloprost appearing intravascularly) decreased from 76% at the lowest to 33% at the highest iloprost dosage. (ii) The pulmonary vasodilatory response commenced already during the nebulization maneuver and preceded the perfusate entry of iloprost. (iii) After 3-3.5 h, the pulmonary vasodilatory response to aerosolized iloprost had virtually completely leveled off, whereas approximately two-thirds of the maximum iloprost perfusate levels were still detectable. A corresponding loss of vasodilatory response was also noted in experiments with continuous iloprost perfusion for clamping of the intravascular concentration of this prostanoid. We conclude that aerosolized iloprost causes dose-dependent vasodilatation and iloprost entry into the vascular space in a pulmonary hypertension model. Limited bioavailability in the higher dose range may suggest active prostanoid transport processes, and the early pulmonary vasodilatory response appears to be independent of prostanoid entry into the vessel lumen. Surprisingly, rapid tolerance development to the vasodilatory effect of iloprost is noted, occurring even with fully maintained perfusate levels of this agent.

Effect of isopregnanolone on rapid tolerance to the anxiolytic effect of ethanol

It has been shown that neurosteroids can either block or stimulate the development of chronic and rapid tolerance to the incoordination and hypothermia caused by ethanol consumption. The aim of the present study was to investigate the influence of isopregnanolone on the development of rapid tolerance to the anxiolytic effect of ethanol in mice. Male Swiss mice were pretreated with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) 30 min before administration of ethanol (1.5 g/kg). Twenty-four hours later, all animals we tested using the plus-maze apparatus. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to the anxiolytic effect of ethanol. In the second, the influence of pretreatment of mice with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) on rapid tolerance to ethanol (1.5 g/kg) was studied. The results show that pretreatment with isopregnanolone interfered with the development of rapid tolerance to the anxiolytic effect of ethanol.

Genetic Dissociation Between Ethanol Sensitivity and Rapid Tolerance in Mouse and Rat Strains Selectively Bred for Differential Ethanol Sensitivity

The Inbred Long- and Short-Sleep mice (ILS and ISS) and the Inbred High- and Low-Alcohol-Sensitive rats (IHAS and ILAS) were selectively bred for differential alcohol sensitivity with use of the duration of loss-of-righting-reflex test (LORR), with the IHAS and ILS animals being much more sensitive than the ILAS and ISS animals, respectively. The current study was undertaken to determine whether acute sensitivity in these strains is genetically correlated to a rapid tolerance to alcohol, a form of tolerance that is evident 24 hr after a single alcohol dose. Separate groups of animals were administered a single pretreatment dose of alcohol (0-6 g/kg for the mice; 0-4 g/kg for the rats). Alcohol sensitivity was tested 24 hr later with the LORR test, and blood ethanol concentration was tested at regain of righting (BECRR). Alcohol-induced hypothermia also was determined in the mice. Independently derived replicate rat strains were used for all experiments (IHAS1, ILAS1; IHAS2, ILAS2); no such replicates exist for the ILS and ISS strains. Alcohol pretreatment caused a dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the ILS strain, but LORR increased in the ISS strain with no effect on BECRR. Both strains became hypothermic during the LORR test on day two, but the only significant effect of alcohol pretreatment was in the ISS strain, in which alcohol-induced hypothermia was enhanced. Alcohol pretreatment caused a significant dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the IHAS1 but not in the IHAS2 strain. In contrast, ILAS1 and ILAS2 strains both showed a significant increase in LORR duration and also a significant increase in BECRR. Alcohol pretreatment caused a dose-dependent decrease in LORR duration and an increase in BECRR in the IHAS1 and ILS strain, suggesting the development of functional rapid tolerance. In contrast, LORR duration increased in the ILAS1, ILAS2, and ISS groups, but BECRR either increased (ILAS1, ILAS2) or did not change (ISS). These observations suggest that central nervous system sensitivity was decreased in the ILAS1 and ILAS2 groups (i.e., rapid functional tolerance) or unchanged in the ISS strain, but that some pharmacokinetic property also was altered in these strains. Overall, the results do not support a genetic relation between alcohol sensitivity and the development of rapid tolerance.

Nicotinic receptor involvement in antinociception induced by exposure to cigarette smoke

Direct exposure of rats to tobacco smoke induces antinociception. We presently investigated if this antinociception is mediated via nicotinic and/or μ-opioid receptors. Adult male rats were surgically implanted with Alzet osmotic minipumps that delivered either saline (control), the nicotinic antagonist mecamylamine, or the opiate antagonist naltrexone (3 mg/kg/day i.v. for 21 days). Nocifensive responses were assessed on alternate days using tail-flick reflex latency (TFL) over a 3-week period. During the second week, the rats were exposed to concentrated cigarette smoke in an environmental chamber for 6 h/day for 5 consecutive days; a control group was similarly exposed to filtered cigarette smoke. Rats receiving mecamylamine and naltrexone exhibited a significant weight loss after the first day of infusion. All treatment groups additionally exhibited significant weight loss during exposure to unfiltered or filtered smoke. The saline group exhibited significant antinociception on the first day of smoke exposure with rapid development of tolerance. The mecamylamine and naltrexone groups did not exhibit significant antinociception. Controls exposed to filtered smoke (with ∼50% lower nicotine concentration) also exhibited significant analgesia on the first exposure day with rapid development of tolerance. Exposure to high levels of cigarette smoke, or to filtered smoke with a lower nicotine concentration in the vapor phase, induces antinociception with rapid development of tolerance. The antinociceptive effect appears to be mediated via nicotinic and μ-opioid receptors.

Systemic and intra-accumbens microinjections of naltrexone interfere with tolerance to ethanol in rats

Evidence suggests a role for the opioid system in the control of ethanol reinforcement and drinking. Previous findings have shown that naltrexone, an opioid antagonist that decreases ethanol consumption in humans and experimental animals, reduces the acquisition of acute ethanol tolerance in rats. However, there are few data regarding the role of the opioid system in the acquisition of ethanol tolerance, particularly in brain areas involved in the rewarding actions of ethanol. This study investigates the effects of systemic and of intra-accumbens injections of naltrexone on the development of rapid tolerance to ethanol. Wistar rats received intraperitoneal injections of naltrexone (0.1-3.0 mg/kg) or microinjections into the core or shell portions of the nucleus accumbens (5-20 microg) before ethanol (2.7 g/kg i.p.). The animals were tested for motor coordination on the tilting plane apparatus. Tolerance was assessed 24 h later by administering the same dose of ethanol to all animals and retesting them on the tilting plane. The second injection of ethanol resulted in less motor incoordination on Day 2, suggesting the development of rapid tolerance. Pretreatment with naltrexone, either i.p. (0.3 and 0.6 mg/kg) or intra-accumbens (5-20 microg), on Day 1, blocked the development of rapid tolerance to the motor-incoordinating effects of ethanol on Day 2 without affecting the motor performance of the animals on Day 1. The results suggest that the opioid system may be involved in the development of ethanol tolerance, and that the nucleus accumbens may play a role in this phenomenon.

Blockade of adenosine and dopamine receptors inhibits the development of rapid tolerance to ethanol in mice

Several reports have suggested the involvement of brain adenosine and dopamine receptors in different actions produced by ethanol such as motor incoordination or anxiolytic, hypnotic and reinforcing effects. The co-localization and interaction between adenosine and dopamine receptors in different brain regions has also been well documented. However, few studies have demonstrated the involvement of these mechanisms in the tolerance induced by ethanol. The aim of the present study was to evaluate the role of adenosine and dopamine receptors in the development of rapid tolerance to ethanol-induced motor incoordination in mice. In connection with the rota-rod apparatus, the effects of acute administration of the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A1 receptor antagonist) and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A2A receptor antagonist), together with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390, dopamine D1 receptor antagonist) and sulpiride (dopamine D2 receptor antagonist), alone or in combination with ethanol (2.25 g/kg, i.p.), were studied. Twenty-four hours after, all animals were re-tested on the rota-rod after receiving the same dose of ethanol. The repeated administration of ethanol promoted a significant reduction of motor impairment on day 2 (i.e. rapid tolerance). This effect was blocked by caffeine (3.0-30.0 mg/kg, i.p.), DPCPX (3.0-6.0 mg/kg, i.p.) or SCH23390 (0.01-0.03 mg/kg, s.c.), but not with ZM241385 (0.5-1.0 mg/kg, i.p.) or sulpiride (1.0-3.0 mg/kg, i.p.). Our results suggest that the rapid tolerance to ethanol-induced motor impairment in mice may be modulated by adenosine A1 receptors and dopamine D1 receptors.

Genetic analysis of rapid tolerance to ethanol's incoordinating effects in mice: inbred strains and artificial selection.

Ethanol tolerance, a decrease in drug responsiveness with repeated administrations, is an important diagnostic criterion for alcoholism. Rapid tolerance develops within 8-24 hours of an initial ethanol exposure and shares many similarities with chronic tolerance. The genetic contribution to rapid tolerance to ethanol-induced ataxia was estimated using a panel of inbred strains of mice. Strains differed significantly in the degree of rapid tolerance development, which had a broad-sense heritability estimate of 0.11. Artificial selection was carried out to develop lines of mice that would show High (HRT) and Low (LRT) levels of Rapid Tolerance. Starting with HS/Npt mice, derived from a systematic cross of eight inbred strains, a significant response to selection was seen in replicate 1 by the third selection generation. No difference was found in replicate 2. Heritability estimates after the fourth generation were 0.25 for HRT-1 mice and 0.06 for LRT-1 mice. HRT-1 and LRT-1 mice also differed significantly in chronic tolerance development to four doses of ethanol. These studies provide evidence for a genetic contribution to rapid tolerance and support a genetic link between rapid and chronic tolerance to ethanol's ataxic effects.

Drunk Worms Reveal Alcohol Tolerance Gene

Davies et al. took advantage of allelic variation in strains of the nematode Caenorhabditis elegans to identify a gene that contributes to tolerance to the effects of ethanol exposure. C. elegans exhibits a decline in locomotor activity as an acute response to ethanol. Over time, in the continued presence of ethanol, different strains of worms, N2 and CB4856, show slow and rapid development of tolerance, respectively. Through genetic analysis, the differences in the rate of tolerance development were mapped to the nrp-1 gene, which encodes the homolog to mammalian neuropeptide Y (NPY) receptors. The CB4856 allele of npr-1 is a lower function allele than that of the N2 worms, and these different alleles of npr-1 are known to account for the worm's differences in social behaviors (N2 are solitary, CB4856 are more social and exhibit clumping behaviors). The social behavior roles of NPR-1 and the ethanol tolerance effect were separable based on genetic interactions and targeted expression studies. Worms carrying mutations in genes involved in controlling social behaviors showed no difference in ethanol tolerance rates. However, ethanol may inhibit NPR-1 signaling, because withdrawal of ethanol causes N2 worms to exhibit clumping and other social behaviors. NPY signaling is implicated in alcohol responsiveness in mammals, and further investigation with the genetically tractable nematode may lead to additional insight into the molecular mechanisms that contribute to alcoholism. A. G. Davies, J. C. Bettinger, T. R. Thilel, M. E. Judy, S. L. McIntire, Natural variation in the nrp-1 gene modifies ethanol responses of wild strains of C. elegans . Neuron 42 , 731-743 (2004). [Online Journal]

Influence of prazosin and clonidine on morphine analgesia, tolerance and withdrawal in mice

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (α 2-adrenoceptor agonist) and prazosin (α 1-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another α 1-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of α 2-adrenoceptors in opioid actions, also α 1-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.

Immune Mechanisms in Pain Control

Immune Mechanisms in Pain Control

Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit.

Stress-related mucosal disease develops in patients in the intensive care unit and can result in clinically important bleeding, which is associated with increased mortality. Patients in the intensive care unit without either mechanical ventilation or coagulopathy, which are the primary risk factors for such bleeding, do not seem to need or to benefit from prophylactic acid suppression for stress-related mucosal disease. Although histamine-2-receptor antagonists significantly reduce clinically important bleeding in patients in the intensive care unit and are widely used for prophylaxis, their benefits are limited by the rapid development of tolerance. Previous data suggested that agents that elevate the intragastric pH may increase the susceptibility of patients in the intensive care unit to nosocomial pneumonia. However, the largest study to date showed that intravenous histamine-2-receptor antagonists may not significantly increase the risk of ventilator-associated pneumonia or mortality compared with sucralfate, an agent that does not affect intragastric pH. Intravenous proton pump inhibitors are more potent and longer-acting inhibitors of gastric acid production than intravenous histamine-2-receptor antagonists. The ability of proton pump inhibitors to prevent stress-related mucosal disease and clinically important bleeding seems to be clinically meaningful. Preliminary findings have shown that intermittent administration of intravenous pantoprazole, the first proton pump inhibitor available by this route in the United States, is as effective in raising intragastric pH on the first day as a continuous infusion of a histamine-2-receptor antagonist in clinical trials conducted within an intensive care unit setting. This suggests that for stress ulcer prophylaxis, intermittent dosing with an intravenous proton pump inhibitor may be an alternative to high-dose continuous infusions of a histamine-2-receptor antagonist. These agents must be compared in clinical trials conducted in an intensive care unit setting.

Effects of intracerebroventricular administration of 7-nitroindazole on tolerance to ethanol

Previous studies have shown that nitric oxide (NO) is involved in the development of rapid tolerance to the motor incoordination produced by ethanol. In order to further investigate this involvement, three experiments were undertaken using the tilt-plane and the hypothermia tests. The first demonstrated that 7-nitroindazole (7-NI), a preferential neuronal NO synthase (nNOS) inhibitor, injected by intracerebroventricular (i.c.v.) route, blocked the development of rapid tolerance to ethanol-induced motor incoordination. This effect was prevented by i.c.v. injection of L-arginine. The second experiment showed that D-arginine did not influence the blockade of tolerance produced by 7-NI. The third experiment revealed that i.c.v. injection of 7-NI also blocked the development of tolerance to the hypothermic effect of ethanol. These results support the hypothesis that nNOS-derived NO participates in the development of rapid tolerance to ethanol.