Suppression Of Withdrawal Research Articles

89EMF The Utility of High Dose Buprenorphine in Producing Prolonged Suppression of Opioid Withdrawal

89EMF The Utility of High Dose Buprenorphine in Producing Prolonged Suppression of Opioid Withdrawal

Physiological dependence to mitragynine indicated by a rapid cross-dependence procedure with heroin-dependent mice.

The potential of mitragynine to produce physiological dependence (withdrawal) was assessed using a rapid assessment procedure with male ICR mice exposed to heroin-admixed food followed by naloxone (subcutaneously, s.c.) precipitation of withdrawal. Initial studies indicated that 3 days of exposure to 3.0 mg/g of heroin-admixed food followed by naloxone (0.6 mg/kg) reliably precipitated withdrawal jumping and weight loss. Lower concentrations of heroin-admixed food and lower doses of naloxone produced fewer withdrawal signs. A longer exposure to heroin-admixed food did not produce significantly greater amounts of jumping or weight loss. Further, these withdrawal signs were dose-dependently reversed by s.c. administration of heroin immediately following naloxone administration. Mitragynine (s.c.) also dose-dependently suppressed naloxone-precipitated withdrawal signs. Additionally, both jumping and weight loss were suppressed over a comparable range of mitragynine doses when administered by gavage with a noticeably, but not significantly, higher potency than with s.c. administration. The ED50 values for mitragynine for the suppression of withdrawal by any route (354-911 μmol/kg) were greater than the minimally effective dose that decreased locomotor activity (251 μmol/kg) and from 40- to 104-fold greater than those for heroin. The results suggest inherent opioid dependence liability of mitragynine. The in vivo potency relations between mitragynine and heroin are consistent with a conclusion of dependence-producing effects, indicated by the suppression of withdrawal, comparable to standard opioid μ-receptor agonists, differing primarily in terms of potency. The present paper provides a method for the rapid assessment of physiological dependence liability applicable to other kratom plant constituents or any potential opioid dependence-producing agents.

Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder

Buprenorphine is an efficacious, widely used treatment for opioid use disorder (OUD). Daily oral transmucosal formulations can be associated with misuse, diversion, and nonadherence; these limitations may be obviated by a sustained release formulation. To evaluate the ability of a novel, weekly, subcutaneous buprenorphine depot formulation, CAM2038, to block euphorigenic opioid effects and suppress opioid withdrawal in non-treatment-seeking individuals with OUD. This multisite, double-blind, randomized within-patient study was conducted at 3 controlled inpatient research facilities. It involved 47 adults with DSM-V moderate-to-severe OUD. The study was conducted from October 12, 2015 (first patient enrolled), to April 21, 2016 (last patient visit). A total of five 3-day test sessions evaluated the response to hydromorphone (0, 6, and 18 mg intramuscular in random order; 1 dose/session/day). After the first 3-day session (ie, qualification phase), participants were randomized to either CAM2038 weekly at 24 mg (n = 22) or 32 mg (n = 25); the assigned CAM2038 dose was given twice, 1 week apart (day 0 and 7). Four sets of sessions were conducted after randomization (days 1-3, 4-6, 8-10, and 11-13). The primary end point was maximum rating on the visual analog scale for drug liking. Secondary end points included other visual analog scale (eg, high and desire to use), opioid withdrawal scales, and physiological and pharmacokinetic outcomes. A total of 46 of 47 randomized participants (mean [SD] age, 35.5 [9] years; 76% male [n = 35]) completed the study. Both weekly CAM2038 doses produced immediate and sustained blockade of hydromorphone effects (liking maximum effect, CAM2038, 24 mg: effect size, 0.813; P < .001, and CAM2038, 32 mg: effect size, 0.753; P < .001) and suppression of withdrawal (Clinical Opiate Withdrawal Scale, CAM2038, 24 mg: effect size, 0.617; P < .001, and CAM2038, 32 mg: effect size, 0.751; P < .001). CAM2038 produces a rapid initial rise of buprenorphine in plasma with maximum concentration around 24 hours, with an apparent half-life of 4 to 5 days and approximately 50% accumulation of trough concentration from first to second dose (trough concentration = 0.822 and 1.23 ng/mL for weeks 1 and 2, respectively, with 24 mg; trough concentration = 0.993 and 1.47 ng/mL for weeks 1 and 2, respectively, with 32 mg). CAM2038 weekly, 24 and 32 mg, was safely tolerated and produced immediate and sustained opioid blockade and withdrawal suppression. The results support the use of this depot formulation for treatment initiation and stabilization of patients with OUD, with the further benefit of obviating the risk for misuse and diversion of daily buprenorphine while retaining its therapeutic benefits. Clinicaltrials.gov Identifier: NCT02611752.

Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice

Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT2CR agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT2CR may represent a new avenue for the treatment of opioid addiction.

Anhedonia as a component of the tobacco withdrawal syndrome.

Animal research suggests that anhedonia is a tobacco withdrawal symptom, but this topic has not been addressed definitively in research with humans. This research sought to determine whether anhedonia is (a) an element of the tobacco withdrawal syndrome in humans and (b) an impediment to successful tobacco cessation. Data were from 1,175 smokers (58.3% women; 85.5% White) participating in a randomized double-blind, placebo-controlled trial of smoking cessation pharmacotherapies. Ecological momentary assessments for 5 days before and 10 days after the target quit day were used to assess anhedonia and other established withdrawal symptoms. Consistent with drug withdrawal, anhedonia showed an inverted-U pattern of change in response to tobacco cessation and was associated with the severity of other withdrawal symptoms and tobacco dependence. Postquit anhedonia was associated with decreased latency to relapse (hazard ratio = 1.09, 95% confidence interval [CI] [1.02, 1.17]) and with lower 8-week point-prevalence abstinence (odds ratio = .91, 95% CI [.86, .97])-relations that remained significant when other withdrawal symptoms were included as predictors. Finally, nicotine replacement therapy nearly fully suppressed the increase in abstinence-related anhedonia (β = -.66, p < .001), suggesting agonist suppression of withdrawal. Results suggest that anhedonia is a unique and motivationally significant element of the tobacco withdrawal syndrome in humans. These results have implications for defining and assessing tobacco use disorder and for understanding and treating tobacco addiction.

Why two smoking cessation agents work better than one: role of craving suppression.

This research examined why smokers receiving combination medication for smoking cessation are more likely to quit smoking than are those who receive either single agent (monotherapy) or placebo. Data were collected from 1,504 current smokers (58.2% women, 83.9% White; mean age = 44.67 years, SD = 11.08) participating in a cessation clinical trial who were randomized to 1 of 6 cessation pharmacotherapy conditions (placebo, nicotine patch, nicotine lozenge, bupropion, nicotine patch + nicotine lozenge, and bupropion + nicotine lozenge). Participants completed ecological momentary assessments 4 times a day, concerning 5 hypothesized mediators (negative affect, positive affect, craving, smoking expectations, and withdrawal) of pharmacotherapy effects. Medications were provided for 8-12 weeks post-quit along with 6 individual counseling sessions. Mediational paths were estimated via a novel Bayesian approach with estimation of multiple mediator models. Biochemically confirmed 8-week abstinence was the outcome variable, with the monotherapy and combination pharmacotherapy composites producing 45% (n = 689) and 54% (n = 478) abstinence rates, respectively. The univariate models suggested that the combination treatments produced higher abstinence rates than the monotherapies because of greater suppression of withdrawal, craving, and smoking expectations. However, multiple mediator models showed that the suppression of craving on the quit day produced the strongest mediational effects and could account for the mediational effects of other tested variables. Suppression of craving on the quit day significantly mediates the clinical effects of monotherapies and combination smoking pharmacotherapies, and the higher abstinence rates for combination therapy versus monotherapies appear primarily due to greater craving suppression.

A double-blind, double-dummy, randomized controlled study of memantine versus buprenorphine in naloxone-precipitated acute withdrawal in heroin addicts

To compare the efficacy of memantine with buprenorphine in the suppression of naloxone-precipitated acute withdrawal in heroin-dependent male subjects in an inpatient setting. Inpatient unit of tertiary level deaddiction facility. Forty-five treatment-seeking heroin-dependent males. Subjects stabilized on 650 mg of dextropropoxyphene for 5 days were randomly divided into two groups on the sixth day: group A (n=25) received 20 mg of memantine with buprenorphineplacebo, and group B (n=20) received 2 mg of buprenorphine with memantine placebo. Acute withdrawals were precipitated with naloxone (0.4 mg, intravenously) and were assessed using subjective and objective opioid withdrawal scales (SOWS and OOWS) and two separate visual analogue scales (VASs) for pain and dysphoria at baseline prior to test drug administration and again after the precipitation of acute withdrawal. Severity ofprecipitated opioid withdrawals. Baseline opioid withdrawal symptoms in both groups did not differ significantly. After the precipitation of acute withdrawal, there were no significant differences between subjects in both groups on OOWS and both VASs but showed significant difference on SOWS. When changes in ratings from baseline (and after naloxone-precipitated acute withdrawal) were compared between the two groups, a significant difference in the change in SOWS scores was observed with greater decrease in withdrawal scores in the buprenorphine group. Memantine has comparable efficacy to buprenorphine in the suppression of objective signs of naloxone-precipitated acute opioid withdrawal; however, its role in the suppression of subjective symptoms is debatable.

Gamma-Hydroxybutyrate Reduces both Withdrawal Syndrome and Hypercortisolism in Severe Abstinent Alcoholics: An Open Study vs. Diazepam

In 42 alcoholic inpatients we performed an open randomized study to compare the effects of diazepam and gamma-hydroxybutyrate (GHB) on the suppression of severe alcohol withdrawal syndrome and hypercortisolism. Both diazepam (.5 mg/kg bodyweight, q.i.d.) and GHB (50 mg/kg bodyweight, q.i.d.) were orally administered for three weeks. During all study period, GHB was more able than diazepam in reducing both withdrawal syndrome and hypercortisolism. These effects were evident during the first week of treatment and persisted throughout the study period. The results confirm a strict correlation between high levels of plasma cortisol and alcohol withdrawal symptoms and they show a slight superiority of GHB over diazepam in the suppression of both ethanol withdrawal and hypercortisolism. Taken together, our data suggest that GHB may act as potent anti-withdrawal agent in severe abstinent alcoholics.

Augmentation of antidepressant response by atypical antipsychotic drugs: electrophysiological studies in the rat brain

Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT2CR agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT2CR may represent a new avenue for the treatment of opioid addiction.

Mechanism responsible for fortnightly modulations in estuarine circulation in Tokyo Bay

The mechanism thought to be responsible for the observed fortnightly modulation of estuarine circulation in Tokyo Bay was investigated in December 1998 using a two-layer theoretical model, which was verified using a three-dimensional non-hydrostatic model. The influence of the difference in kinetic energy between the upper and lower layers on estuarine circulation was clarified in terms of vorticity, which was defined by the difference in the velocities of the two layers. The ratio of the difference in kinetic energy between the two layers to the baroclinic energy was attributed to the change in strength of estuarine circulation. Thus, the mechanism for fortnightly modulations of estuarine circulation may be due to the suppression of upper-water withdrawal during spring tide, when the ratio is more than 1, and the enhancement of upper-water withdrawal during neap tide, when the ratio is close to 0.

A double-blind, double-dummy, randomized, prospective pilot study of the partial Mu opiate agonist, buprenorphine, for acute detoxification from heroin

The optimum dose of buprenorphine for acute inpatient heroin detoxification has not been determined. This randomized, double-blind, double-dummy, pilot study compares two buprenorphine sublingual tablet dosing schedules to oral clonidine. Heroin users ( N = 30) who met DSM-IV criteria for opioid dependence and achieved a Clinical Opiate Withdrawal Scale (COWS) score of 13 (moderate withdrawal), were randomized to receive higher dose buprenorphine (HD, 8-8-8-4-2 mg/day on days 1–5), lower dose buprenorphine (LD, 2-4-8-4-2 mg/day on days 1–5), or clonidine (C, 0.2-0.3-0.3-0.2-0.1 mg QID on days 1–5). COWS scores were obtained QID. Twenty-four hours after randomization, the percentages of subjects who achieved suppression of withdrawal, as defined by four consecutive COWS scores <12, were: C = 11%, LD = 40%, and HD = 60%. Generalized estimating equation regression models, controlling for baseline COWS and time, indicated that COWS scores over the course of 5 days were lower in both LD and HD compared to C ( χ 2(2) = 13.28, P = 0.001). Similar analyses examining scores over time on the Adjective Rating Scale for Withdrawal (ARSW) and on a Visual Analog Scale of Opiate Craving (VAS) indicated an overall treatment effect on the VAS accounted for by a significant difference between HD and C, but no overall treatment effect on the ARSW. There were no discontinuations due to treatment-related adverse events. Both HD and LD regimens are safe and efficacious treatment for opioid detoxification, but HD demonstrated superiority to C on a greater number of measures.

Gabapentin: The First Preemptive Anti-Hyperalgesic for Opioid Withdrawal Hyperalgesia?

Departments of Anesthesiology and Pharmacology &amp; Toxicology, Queen's University, Kingston, Ontario, Canada. gilroni@post.queensu.caIn Reply:—The above letter responds to the provocative question of whether gabapentin is a “broad spectrum” analgesic 1and appropriately points out that things are not quite so simple.Gustorff et al. postulate that the effects of gabapentin reported by Dirks et al. 2are not due to antinociception but, rather, to the suppression of hyperalgesia caused by withdrawal from intraoperative opioids. This is a reasonable hypothesis; however, it should be noted that Fassoulaki et al. recently observed similar reductions in pain and opioid consumption with gabapentin in patients who received no intraoperative opioids. 3Therefore, gabapentin's effects cannot be solely due to suppression of opioid withdrawal hyperalgesia.Nevertheless, this raises questions central to understanding the modulation of pain by gabapentin. While Gustorff et al. correctly indicate that postoperative pain is predominantly nociceptive, they fail to emphasize the importance of spinal sensitization, 4which contributes to hyperalgesia and allodynia and which may be suppressed by gabapentin. Indeed, although gabapentin has little antinociceptive effect in the uninjured organism, it has been shown, in the absence of opioids, to reduce pain responses after surgical tissue injury. 5The latter comments by Gustorrf et al. illustrate the complexities of interpreting gabapentin's effect when administered with opioids. Ethical conduct of most postoperative trials requires the provision of rescue analgesia, often in the form of patient-controlled analgesia with morphine, which necessitates the integration of pain measures with morphine consumption as co-relevant outcome measures. 6Although trials have been equivocal thus far, 7,8the possibility that mechanisms of opioid tolerance 9contribute to postoperative hyperalgesia and increased opioid requirements may confound results of analgesic trials. Therefore, gabapentin trials involving concomitant morphine administration must be interpreted in light of a possible interaction between these drugs. In this regard, we have observed in the rat that gabapentin prevents the development of morphine tolerance and partially reverses established tolerance indicating that such an interaction indeed exists. 10Thus, although follow-up studies will further characterize the role of gabapentin in postoperative pain, even more sophisticated strategies are needed to distinguish between its specific pharmacological effects (e.g. , analgesia, antihyperalgesia, antiallodynia and reversal of opioid tolerance).

Suppression of acute and chronic opioid withdrawal by a selective soluble guanylyl cyclase inhibitor

Previous studies have shown that activation of N-methyl- d-aspartate (NMDA) receptors and formation of nitric oxide (NO) contributes to the hyperactivity of locus coeruleus (LC) noradrenergic neurons and behavioural symptoms seen during opioid withdrawal. However, the role of soluble guanylyl cyclase (sGC), the `physiological' target of NO, in this phenomenon is unclear. In this study, the effect of 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), a highly selective sGC inhibitor, on the naloxone-precipitated morphine withdrawal was examined using differential normal pulse voltammetry (DNPV) to measure LC activity, in vivo microdialysis to measure glutamate/aspartate release response, and behavioural assessment to evaluate withdrawal symptoms. In halothane-anaesthetized rats, acute intracerebroventricular (i.c.v.) morphine (10 μg) reduced the catecholamine oxidation current (CA·OC) (54.5±4.9% of baseline). Naloxone (2 mg/kg, i.v.) reversed this action of morphine and produced a rebound increase in CA·OC (136.1±6.0% of baseline), representing acute morphine withdrawal. Administration of ODQ (200 nmol, i.c.v.) blocked this response without affecting acute morphine action. In animals chronically treated with morphine (15 μg/μl/h, i.c.v., 5 days), naloxone significantly increased both the CA·OC signal (270.0±19.6% of baseline) and the release of l-glu (193±30.4%) and l-asp (221.5±28.4%) above baseline. These responses were attenuated in animals pretreated with ODQ. In unanaesthetized chronic morphine dependent rats, ODQ treatment suppressed the signs of withdrawal precipitated by naloxone (10 mg/kg). Taken together, the results of this study suggest that sGC plays an intermediary role in the genesis of LC neuronal hyperactivity and behavioural signs of morphine withdrawal.

Short-acting NMDA receptor antagonist MRZ 2/576 produces prolonged suppression of morphine withdrawal in mice.

The present study sought to evaluate the time-course of the effects of a short-acting glycine site NMDA receptor antagonist, MRZ 2/576 (half-life of about 20 min), on the expression of morphine withdrawal syndrome in mice. Morphine-naive and morphine-dependent mice (10-100 mg/kg, b.i.d., s.c., 9 days) were injected with a combination of naltrexone (vehicle or 1 mg/kg, s.c.) and MRZ 2/576 (vehicle, 0.3-10 mg/kg, i.p.) 24 h after the last morphine injection. MRZ 2/576 suppressed expression of several signs of morphine withdrawal (jumping, shaking, forelimb tremor). Effects of MRZ 2/576 were equally expressed throughout 1-h observation test of both spontaneous and naltrexone-facilitated withdrawal. These results suggest that despite its short half-life, MRZ 2/576 produces prolonged suppression of morphine withdrawal syndrome and this effect cannot be attributed to repeated morphine-induced increase in sensitivity to naltrexone.

Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and κ-opioid receptor implicated

Our previous work has demonstrated that 100-Hz electroacupuncture (EA) or 100-Hz transcutaneous electrical nerve stimulation (TENS) was very effective in ameliorating the morphine withdrawal syndrome in rats and humans. The mechanism was obscure. (1) Rats were made dependent on morphine by repeated morphine injections (5–140 mg/kg, s.c., twice a day) for eight days. They were then given 100-Hz EA for 30 min 24 h after the last injection of morphine. A marked increase in tail flick latency (TFL) was observed. This effect of 100-Hz EA could be blocked by naloxone (NX) at 20 mg/kg, but not at 1 mg/kg, suggesting that 100-Hz EA-induced analgesia observed in morphine-dependent rats is mediated by κ-opioid receptors. (2) A significant decrease of the concentration of dynorphin A (1–17) immunoreactivity (-ir) was observed in the spinal perfusate in morphine-dependent rats, that could be brought back to normal level by 100-Hz EA. (3) 100-Hz EA was very effective in suppressing NX-precipitated morphine withdrawal syndrome. This effect of EA could be prevented by intrathecal administration of nor-BNI (2.5 μg/20 μl), a κ-opioid receptor antagonist, or dynorphin A (1–13) antibodies (25 μg/20 μl) administered 10 min prior to EA. In conclusion, while the steady-state spinal dynorphin release is low in morphine-dependent rats, it can be activated by 100-Hz EA stimulation, which may be responsible for eliciting an analgesic effect and ameliorating morphine withdrawal syndrome, most probably via interacting with κ-opioid receptor at spinal level.

Effects of Intrathecal Nonnarcotic Analgesics on Chronic Tactile Allodynia in Rats: α&lt;SUB&gt;2&lt;/SUB&gt;-Agonists versus Somatostatin Analog

The effects of the intrathecal alpha 2-agonists tizanidine and clonidine and the somatostatin analog octreotide on an experimental rat model of tactile allodynia were investigated to determine the therapeutic potential for treating chronic neuropathic pain. Allodynia was induced by ligating the rat sciatic nerve. The mechanical threshold for paw withdrawal was assessed by applying von Frey hairs to quantify analgesic actions. Mean 50% paw withdrawal thresholds were converted to the percentage of maximum possible effect (%MPE) where %MPE = (postdrug threshold-predrug threshold) divided by (15 g-predrug threshold) x 100. Dose-response curves were plotted for suppression of paw withdrawal 30 minutes after intrathecal injection of various doses of tizanidine, clonidine, and octreotide. Thresholds on the non-lesioned side were greater than 15 g. The lesioned side had baseline thresholds of less than 4.5 g. Dose-response curves were established for the antiallodynia effects of each drug. Tizanidine and clonidine at a 25-micrograms dose increased the threshold to greater than 97% of the MPE, but caused transient hindpaw weakness or sedation. No side effect was observed at a 10-micrograms dose, at which the threshold was 88-96% of MPE. Intrathecal octreotide modestly increased the threshold to only 49-67% of MPE, showing a lesser analgesic effect, although no side effect was observed at a 4-micrograms dose. The antiallodynic effects of intrathecal tizanidine and clonidine were more potent than that of octreotide.

Midbrain suppression of limb withdrawal and tail flick reflexes in the rat: correlates with descending inhibition of sacral spinal neurons.

1. The aim of this study was to utilize new quantitative behavioral methods in rats to investigate the effects of electrical stimulation in midbrain analgesia areas on the magnitude of flexion hindlimb withdrawal and tail flick reflexes evoked by graded noxious heating. Electrophysiological experiments were then done with the use of these animals to correlate behavioral data with the effects of identical midbrain stimulation on sacral dorsal horn neuronal responses to graded heating of the tail. 2. To quantify limb withdrawals, electromyographs (EMGs) were recorded in biceps femoris during withdrawals elicited by noxious heat stimuli (40-52 degrees C, 5 s, 2-min intervals) delivered to the plantar surface of the hind paw, without and during concomitant electrical stimulation (100 ms, 100-Hz trains, 3/s, 10-600 microA) in midbrain periaqueductal gray (PAG) or laterally adjacent reticular formation (LRF) via previously implanted electrodes. The same animals were tested with the use of a tail flick paradigm modified to allow measurement of the force of tail movements in three orthogonal planes and thereby calculate the overall force vector of tail flicks elicited by graded noxious radiant heat pulses (38-58 degrees C, 5 s, 2-min intervals) delivered to the tail, again with and without concomitant PAG or LRF stimulation. Finally, the same rats were anesthetized with pentobarbital sodium and microelectrode recordings made from single sacral dorsal horn neurons responsive to the same noxious heat stimuli delivered to the tail to assess effects of PAG and LRF stimulation. 3. PAG and LRF stimulation suppressed the magnitude of limb flexor EMGs, and tail flick force vectors, in an intensity-dependent manner. Recruitment of suppression of both limb withdrawal EMGs and tail flicks was generally more effective for LRF compared with PAG stimulation, although mean thresholds for suppression were similar. Tail flick force and limb withdrawal EMGs recorded from the same rat in separate sessions were suppressed about equally in a majority of cases. 4. Limb withdrawal EMG magnitude increased monotonically from threshold (approximately 40 degrees C) to 52 degrees C. The population stimulus-response function was fit equally well by linear regression or a 2 degrees polynomial function (r2 = 0.79 for both). PAG stimulation significantly reduced the mean slope of the stimulus-response function (to 73%; n = 15), whereas LRF stimulation shifted it toward the right with a smaller slope reduction (to 85%) and 3 degrees C increase in threshold.(ABSTRACT TRUNCATED AT 400 WORDS)

Suppression of opiate withdrawal by cyclosporin A and dietary modification

It has been demonstrated in a murine model that a defined diet (Purina Basal Diet 5755) has immunosuppressive effects similar to cyclosporin A (CsA). It was also shown that CsA treatment in opiate dependent rats can attenuate the severity of opiate withdrawal. In this study, an opiate dependence model was established in Balb/c mice to assess the effects of the 5755 diet and CsA on morphine withdrawal - a CNS mediated phenomenon. Three groups of mice were used; a chow-fed control group (Purina 5008), a chow fed CsA treated group, and a group maintained on the 5755 diet. Morphine dependence was established by subcutaneous implantation of a 100 mg morphine base pellet under ether anesthesia. Seventy-two hours after pellet implantation, withdrawal was precipitated by a single injection of the opiate antagonist naloxone (2 mg/kg ip). Two indicators of withdrawal were assessed; jumping and diarrhea. The data demonstrated that both CsA and the 5755 diet resulted in significant attenuation of withdrawal symptoms with the 5755 diet being the most effective of the two. These findings suggest that immune modulation elicited by the 5755 diet and CsA treatment has a direct impact on the CNS opioid function.

The suppression of deprivation and antagonist-induced withdrawal in morphine-dependent rhesus monkeys

The capacity of morphine to suppress natural and precipitated withdrawal was compared in morphine-dependent rhesus monkeys. A similar severity of withdrawal was induced by 14-hr deprivation or precipitated by naloxone, naltrexone, cyclazocine, Win 44,441 or MR 2266. Regardless of the procedure used to induce withdrawal, behavioral signs were completely suppressed by a cumulative dose of 17.5 mg/kg morphine. Thus, an equivalent level of withdrawal induced by reversible antagonists is as sensitive to subsequent morphine administration as is deprivation-induced abstinence. This is in accordance with the theory that vacancy of opiate receptors normally occupied by morphine is related to the level of abstinence observed. In contrast to Win 44,441, however, an equivalent level of withdrawal precipitated by buprenorphine required 175 mg/kg morphine for complete suppression. This is more informative than comparing duration of action; when given as 24-h pretreatments, a high dose of Win 44,441 (10 mg/kg) was only slightly less effective than buprenorphine (3.2 mg/kg) in antagonizing morphine-induced stupor in normal monkeys. Comparison of the ability of morphine to suppress precipitated withdrawal provides evidence of the relative reversibility of antagonists in vivo and demonstrates the extraordinarily stable nature by which buprenorphine acts at opiate receptors.

Dorsal noradrenergic bundle lesions fail to alter opiate withdrawal or suppression of opiate withdrawal by clonidine

Previous work has shown that clonidine effectively supresses many of the signs of opiate withdrawal. The present study was designed to test the hypothesis that the supression of opiate withdrawal by clonidine is mediated by forebrain noradrenergic projections of the locus coeruleus. Two groups of 24 rats each were subjected to either a 6-hydroxydopamine lesion of the dorsal noradrenergic bundle (Lesion group) or a sham, vehicle injection (Sham group). All rats were made dependent on morphine by subcutaneous implantation of one 75 mg silastic morphine pellet for three days followed by 3 more days with two additional 75 mg pellets. Following removal of the morphine pellet, withdrawal was precipitated in all rats by subcutaneous injection of 4 mg/kg of naloxone. Pretreatment 10 min. before withdrawal with clonidine (0.1 or 0.2 mg/kg) produced a significant attenuation of withdrawal signs as compared to saline injected rats; this effect was equally significant in both sham and lesion groups. Lesions of the locus coeruleus had no effect on withdrawal, nor did they affect the ameliorating action of clonidine. These results substantiate the observation that clonidine can effectively attenuate signs of opiate withdrawal in the rat, but fail to support the hypothesis that these effects are mediated by the forebrain projections of the locus coeruleus.