Curve Of Morphine Research Articles

Progressive ratio responding for morphine is differentially altered in the presence of chronic peripheral neuropathy in male vs. female C57Bl/6 mice

s / Drug and Alcohol Dependence 146 (2015) e34–e117 e49 prescription opioid of demonstrated abuse potential, the current study was designed to determine if SVA, when contingently administered with the mu agonist, oxycodone, could reduce the reinforcing effectiveness of oxycodone. Methods: Male rhesus monkeys (n=3) were trained to selfadminister cocaine (0.1 or 0.2mg/kg/inj) under a progressive-ratio (PR) schedule of reinforcement with alternating saline sessions. Once self-administration was stable, tests were inserted into the sequence. Test conditions consisted of a range of doses of oxycodone alone (0.006–0.1mg/kg/inj) or oxycodone mixed with a dose of SVA mg/kg/inj). Results: Oxycodone self-administration resulted in biphasic dose response functions, with the highest breakpoint occurring at the 0.05mg/kg dose in all three monkeys. Combining SVA with oxycodone resulted in rightward and downward shifts in the doseresponse functions for oxycodone, indicating a decrease in both the potency and effectiveness of oxycodone as a reinforcer. Conclusions: Our findings demonstrate that SVA, when contingently administered with oxycodone, decreases the reinforcing effectiveness of oxycodone under the current PR schedule conditions. Addingkappa agonists to prescriptionopioidsmaybe a viable abuse-deterrent formulation strategy. Financial support: This research was supported by grants R01DA-027666 to KBF and R01-DA-018151 to TEP from the National Institute on Drug Abuse. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.503 Progressive ratio responding for morphine is differentially altered in the presence of chronic peripheral neuropathy in male vs. female C57Bl/6 mice Harshini Neelakantan, Sara J. Ward, Ellen A. Walker Temple University, Philadelphia, PA, United States Aims: Clinical management of chronic pain with prescription opioids remains a challenge due to concerns about opioid-induced dependence and addiction. Sex-differences in pain sensitivity, opioid analgesia, and reinforcing effects of opioids are observed in rodents. The purpose of our study is to test the hypothesis that the presence of paclitaxel-induced chronic peripheral neuropathy will differentially alter the sensitivities of male and female mice to morphine-induced reinforcing effects. Methods: Male and female C57Bl/6 mice were implanted with indwelling catheters and trained to self-administer morphine under a progressive ratio (PR) schedule of reinforcement. Following stable responding,micewere treatedwith saline or paclitaxel (PAC) and tested formorphine (0.01–0.1mg/kg/inf) responding under PR. Results: PAC treatment produced higher breakpoints for morphine that increased progressively with the development of allodynia in male but not in female mice. A significant upward shift in the dose-effect curve for morphine was observed in the PAC-treated male mice. While only the PAC-treated male mice demonstrated an increase in motivation to respond for morphine, increases in the PR responding for morphine were observed in both in the salineand PAC-treated female groups. The cumulative records from the self-administration sessions displayed marked differences in the pattern of drug-taking behavior in the PAC versus controlmalemice. Further, PAC-treatedmalemicedisplayed increased intake of the prescription opioidmorphine in the state of chronic pain compared to their saline-treated counterparts. Conclusions: The reinforcing effects and the motivational salience of morphine are altered by the presence of paclitaxelinduced peripheral neuropathy with male mice displaying greater sensitivity to these effects compared to female mice. Overall, these results may have implications for the understanding of potential sex differences in the clinical management of pain and the genderdependent abuse liability of prescription opioids in humans. Financial support: Supported by R01 CA129092. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.504 Patterns of crack use among drug-using females in Mexico city Nalini Negi1, Avelardo Valdez2, Alice Cepeda2, Guillermina Natera3 1 School of Social Work, University of Maryland, Baltimore, Baltimore, MD, United States 2 School of Social Work, University of Southern California, Los Angeles, CA, United States 3 Instituto de Psiquiatria, Ramon de la Fuente Muniz,

Morphine Inhalation by Cancer Patients: A Comparison of Different Nebulization Techniques Using Pharmacokinetic, Spirometric, and Gasometric Parameters

Despite numerous case reports suggesting the value of morphine (M) nebulization in the treatment of breathlessness, only a few clinical trials have been able to support this. The reason for this could lie in the lack of understanding of the localization of opioid receptors in the airways and the biopharmaceutics and pharmacokinetics of nebulized morphine. In the present study, we compared two different methods of pneumodosimetric nebulization: the Bronchial Control Treatment System-Sidestream (BCTS-S) and the Bronchial Control Treatment System-Micro Cirrus (BCTS-MC). The first method delivers relatively large aerosol particles (2–5 μm) preferentially to the bronchial tree and trachea. In the BCTS-MC method, small aerosol particles (0.5–2 μm) mostly reach the alveoli. Ten patients with cancer were randomly assigned to either the BCTS-S or BCTS-MC inhalation of 5 mg morphine HCl. Patients using the BCTS-S method inhaled a morphine dose in 6.6 ± 2 minutes, whereas with the BCTS-MC method, the inhalation time was 28.8 ± 8 minutes. The areas under the curve of morphine and glucuronides were several times higher after BCTS-S than after BCTS-MC. The proportion of morphine-3-glucuronide to morphine-6-glucuronide (M6) was, on average, close to one for both methods. From the same amount of morphine in the BCTS-S method, five times more M6 was produced. In both methods, the time to maximum concentration for morphine metabolites was 20–40 minutes, much shorter than expected from oral, intranasal, or intravenous administration. The study shows that the method of inhalation may have a profound effect on the pharmacokinetics of morphine. It is possible that the lungs metabolize morphine to glucuronides themselves and in different proportions from those seen after systemic administration. The BCTS-S method was found to be potentially superior to the BCTS-MC method in local action in the lungs.

A Double-Blind, Randomized, Crossover Comparison Between Single-Dose and Double-Dose Immediate-Release Oral Morphine at Bedtime in Cancer Patients

The European Association for Palliative Care guidelines for treatment of cancer pain recommend a double dose (DD) of immediate-release morphine at bedtime instead of single doses (SD) repeated every four hours throughout the night. A previous open controlled study reported more side effects after DD than after SD. The present study was a randomized, double-blind, crossover study comparison of DD and SD of immediate-release morphine during the night, followed by an open pharmacokinetic study. The primary outcome was average pain intensity during the night, as measured on an 11-point numerical rating scale. Secondary outcomes were morning pain, number of rescue medications, adverse effects (nausea, xerostomia, tiredness, sleep quality, and number of awaking episodes) and patient preference. Morphine and metabolites were quantified by a validated liquid chromatography-tandem mass spectrometry method. Nineteen patients completed the clinical study; 13 participated in the pharmacokinetic follow up. Average pain during the night for DD vs. SD was close to statistical significance (mean 0.8 and 1.4, respectively, P = 0.058; mean [95% confidence interval] for the difference was 0.50 [0.02, 1.0]). A similar trend was observed for strongest night pain ( P = 0.069) and sleep quality ( P = 0.077). Only two patients required rescue morphine. Four patients had no treatment preference; nine and six favored DD and SD, respectively. DD patients displayed higher area under the curve for morphine and morphine-6-glucuronide during the first part of the night. Although DD tended to perform slightly better than SD, a difference in average pain during the night of 0.50 has little clinical significance, and the two procedures are, therefore, clinically equivalent. It is speculated whether the initial higher exposure to morphine-6-glucuronide may have clinical significance.

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.

Discriminative-stimulus control by morphine in the pigeon under a fixed-interval schedule of reinforcement

The stimulus control by morphine under a fixed-interval (FI) 180-s schedule of reinforcement was examined in five pigeons trained to discriminate 5.0mg/kg of i.m. morphine from saline. After training, dose-response relationships were determined for morphine, d-amphetamine, pentobarbital, fentanyl, and MK-801. At low doses of morphine, responding of individual subjects was predominantly on the saline-appropriate key. At intermediate doses responding occurred on both keys throughout the interval. Following doses of 5.6mg/kg and higher, responding on both keys was observed in the early portions of the interval with responding shifting to the morphine-appropriate key as the interval progressed. Thus, a graded dose-effect curve for morphine was obtained under the FI schedule. The fentanyl dose-effect curve was similar to that obtained with morphine, but the other test drugs were not generalized. Five other pigeons were trained to discriminate 5.0mg/kg of morphine from saline under a fixed-ratio (FR) 100 schedule of reinforcement. During testing with morphine, responses were confined to the saline-appropriate key at 0.3 and 1.0mg/kg of morphine, but at higher doses responses were confined to the drug key. In contrast to the results obtained using the FI schedule, a quantal relationship for responding on the two keys was observed when a FR schedule was employed.

Potentiation of morphine analgesia in rats given a single exposure to restraint stress immobilization

Rats exposed to restraint stress and injected with morphine show significantly greater increases in tail-flick latency compared to unstressed rats. However, it is not necessary for rats to be restrained at the time of testing to elicit a potentiated analgesic response to morphine. We reported recently that analgesia induced by 4.0 mg/kg morphine was significantly potentiated in rats that had been restrained for only 1 h at 24 h prior to testing. One purpose of the present study was to extend this observation by determining the ability of a single exposure to restraint stress to potentiate dose-dependently morphine (0.0, 2.0, 4.0, and 8.0 mg/kg)-induced analgesia in the tail-flick test. A second purpose was to assess the generality of the phenomenon by determining whether prior restraint would potentiate the analgesic effect of morphine in another common analgesic assay, the hot-plate test. Dose- and time-course (20–120 min) curves for morphine were generated in rats exposed to one of two treatments: no restraint stress (NS) and a single exposure to 1 h of restraint (RS). Rats subjected to 1 h of restraint and tested 24 h later displayed significant time- and dose-dependent potentiation (1.3–2.0-fold) of morphine-induced analgesia compared to unstressed rats in both the tail-flick and hot-plate tests. These results demonstrate that a single period of restraint is sufficient to active to the mechanisms responsible for potentiation of morphine-induced analgesia and that the degree to which stress modifies morphine's analgesia can be demonstrated using both the tail-flick and hot-plate assays.

Factors affecting restraint stress-induced potentiation of morphine analgesia

The analgesic effect of opioid drugs is potentiated in rats exposed to restraint stress as compared to unstressed rats. The purpose of the present study was to quantify how the following factors affect morphine-induced analgesia: habituation to restraint versus exposure to restraint for the first time, restraint stress duration, and interval from restraint to analgesic testing. Expts. 1 and 2 generated dose- and time course curves for morphine in rats exposed to one of 3 treatments: no restraint stress (NS), first exposure to 1 or 6 h of restraint (FS), or 5 days of restraint habituation followed by 1 or 6 h of restraint on the test day (HAB). Analgesia was measured by the tail-flick assay. Rats subjected to 1 h of restraint displayed dose- and time-dependent potentiation of morphine-induced antinociception compared to unstressed rats. Given 4.0 mg/kg morphine, FS-treated subjects showed 1.4- and 2.7-fold more potentiation of analgesia than HAB- and NS-treated rats, respectively. Rats restrained for 6 h prior to testing showed significant dose effect for morphine but failed to reveal significant treatment effects. Thus, increasing the duration of restraint from 1 to 6 h attenuated morphine antinociception in FS- and HAB-treated subjects to the level of NS subjects. In Expt. 3, several groups of rats underwent a single 1-h session of restraint at various time intervals prior to injection with morphine (4.0 mg/kg) and tail-flick testing. An unstressed group also receiving morphine served as control. Rats restrained at 0.5, 24, 48 and 168 h prior to testing showed significant potentiation of morphine-induced antinociception, with peak potentiation (twice the level of antinociception) occurring at 24 h after restraint. Thus, previous exposure to restraint, the duration of restraint, and interval between restraint and analgesia testing affect the degree to which stress modifies morphine-induced analgesia.

Analgesia and decrement in operant performance in socially defeated mice: selective cross-tolerance to morphine and antagonism by naltrexone.

During a social confrontation between a resident and an intruder mouse, only the submissive or defeated intruder shows an opioid-mediated analgesia to which tolerance develops. We investigated the altered morphine responsiveness after different kinds of social experiences. Mice were assessed for performance of operant behavior under the control of a fixed ratio schedule of positive reinforcement as well as for the tail flick response to a heat stimulus before and after one or five consecutive social confrontations. The dose-effect curves for morphine's suppression of schedule-controlled behavior were closely similar before and after defeat in a single or in five social confrontations. However, the concurrently measured response to pain in the tail flick assay produced morphine dose-effect curves that were shifted to the right after defeat in one or five social confrontations. Four to six times higher doses of morphine were necessary to produce analgesia in mice that were defeated in five social confrontations. Naltrexone (1 mg/kg, ip) antagonized the suppressive effects of morphine (10 mg/kg, ip) on rate of responding and the analgesic effects. Naltrexone also blocked the development of analgesia in mice that were defeated for the first time in a social confrontation, but did not prevent the suppressive effects on rate of responding. Specific social experiences such as defeat in a social confrontation appear to alter endogenous opioid process that mediate analgesia; these processes differ from those that suppress positively reinforced behavior. The differential development of morphine tolerance to the analgesic effects, but not the rate-decreasing effects as well as the differential naltrexone antagonism of both effects may indicate the involvement of opioid and non-opioid mechanisms.

Presynaptic effects of scopolamine, oxotremorine, noradrenaline and morphine on [3H] acetylcholine release from the myenteric plexus at different stimulation frequencies and calcium concentrations

The inhibition by three modulators (oxotremorine, noradrenaline, morphine) of acetylcholine release from the myenteric plexus preincubated with [3H]choline was investigated at different stimulation frequencies and calcium concentrations. Moreover, [3H]acetylcholine release evoked by a low (0.1 Hz) or a high (10 Hz) stimulation rate was investigated at different calcium concentrations either in the absence or presence of scopolamine. A reduced calcium concentration (0.6 mmol/l) inhibited acetylcholine release more at 0.1 Hz (74% +/- 3%) than at 10 Hz (44% +/- 8%). Scopolamine enhanced the stimulated acetylcholine release at a calcium concentration of 1.8 mmol/l. At calcium concentrations higher than 1.8 mmol/l scopolamine failed to enhance transmitter release markedly. A reduction of the calcium concentration (less than 1.8 mmol/l) significantly enhanced the effect of scopolamine, when acetylcholine release was evoked at 0.1 Hz. Oxotremorine (10 mumol/l) completely suppressed acetylcholine release at 1 Hz (120 pulses). When 120 pulses were applied at 10 Hz the maximal effect was only a 64% inhibition and the concentration-response curve was significantly shifted to the right. However, after a reduction of both the train length or the calcium concentration oxotremorine produced a complete inhibition of acetylcholine release evoked at 10 Hz. In contrast to the effect of oxotremorine, the concentration-response curves for morphine and noradrenaline were similar at 1 Hz and 10 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation of tolerance and dependence to morphine: a possible role for cholecystokinin

Since cholecystokinin (CCK) has been suggested to be an endogenous opiate antagonist, we tried to evaluate if this peptide could be involved in the development of tolerance to morphine. Naive rats were chronically administered morphine, either alone or concomitantly with proglumide or benzotript, two putative CCK receptor antagonists. Chronic treatments with both CCK antagonists alone were also established. Drugs were administered by the oral route, dissolved in the drinking water. At the end of the chronic treatments, the development of tolerance to morphine was assessed by an evaluation of the analgesic responses evoked by graded doses of acutely injected morphine in the tail-flick and hot plate tests. Proglumide and benzotript were able to inhibit the shift to the right of the dose-response curve for morphine, i.e. they prevented the development of tolerance to morphine-induced analgesia. Chronically given alone, the two CCK antagonists never modified the responses to the acute challenge with morphine. We also determined the development of physical dependence by looking at the withdrawal syndrome precipitated by graded doses of acutely injected naloxone. In these experiments the concomitant treatment with morphine and proglumide or benzotript did not modify the occurrence of dependence. These observations are consistent with the hypothesis of CCK being an endogenous opiate antagonist, involved in the development of tolerance to morphine-induced analgesia but not of dependence. Moreover, tolerance to and dependence on morphine can be pharmacologically dissociated.

Microwave Facilitation of Methylnaltrexone Antagonism of Morphine-Induced Analgesia in Mice

Exposure to low dose microwave irradiation has been postulated to influence effects of centrally active pharmacological agents. In this investigation, the analgesic dose, 50% (ADSO) for morphine in the mouse tail flick test was significantly increased by pretreatment with the centrally active opiate receptor blocker naltrexone, and the dose-response curve ms shifted significantly to the right. On the other hand, the AD50 and dose-response curve for morphine were not influenced by either the peripherally active opiate receptor blocker methylnaltrexone alone or microwave irradiation (2.45 GHz, 20 mW/cm2, CW, 10 min) alone. However, following both methylnaltrexone pretreatment and microwave exposure, there was both a significant increase in the AD50 as well as a significant rightward shift of the dose-response curve, indicating a competitive antagonism of morphine by methylnaltrexone. One possible explanation for this microwave-drug interaction is that microwave energy might facilitate entry of methylnaltrex...

Effects of ketocyclazocine and ethylketocyclazocine on electric shock titration

The effects of two putative κ agonists, ketocyclazocine and ethylketocyclazocine, on electric shock titration in squirrel monkeys were determined. Drugs were tested alone, in combination with naloxone and following the development of morphine tolerance. Both ketocyclazocine and ethylketocyclazozine produced biphasic dose-effect curves. Low doses decreased whereas high doses increased the intensity at which monkeys maintained the shock. Naloxone antagonized the effects of ketocyclazocine and ethylketocyclazocine; however, the dose of naloxone required to antagonize their effects was much larger than the dose required to antagonize equivalent effects of morphine. When the effects of ethylketocyclazocine were redetermined in monkeys tolerant to morphine, the ethylketocyclazocine dose-effect curve was shifted to the left whereas the morphine curve was shifted to the right. It was concluded that the effects of the κ agonists can be differentiated from morphine by the shape of their dose-effect curve, the ease with which they are antagonized by naloxone and the lack of cross tolerance to morphine.

Analgesic Properties of Lidocaine in Mice

The analgesic properties of lidocaine and morphine were compared in mice using a hot plate stimulus. An analgesic response was defined as an increase in the time required for an animal to attempt to escape by jumping. When compared to saline-treated controls, lidocaine produced a statistically significant dose-related delay in response to heat. Dose-response curves for morphine and lidocaine indicated that morphine has greater potency and efficacy. Naloxone (1.0 mg/kg) reversed the analgesic response due to morphine (10 mg/kg) but had no effect on the analgesia produced by lidocaine (50 mg/kg).

The effect of narcotic analgesics and their antagonists on conditioned avoidance in the rat.

SUMMARY 1. To investigate the hypothesis that some degree of tranquillizer activity is a necessary component of analgesic activity, several narcotic analgesic drugs and narcotic antagonists were tested for their ability to block a conditioned avoidance response in rats, and their actions were compared with those of chlorpromazine and chlordiazepoxide. 2. Morphine, oxymorphone, oxycodone and codeine specifically blocked the avoidance response in a dose-dependent manner, in doses comparable with those having antinociceptive action. Neither nalorphine nor naloxone had any significant effect on the avoidance response, but they caused a parallel shift of the dose-response curve of morphine to the right. 3. Pentazocine specifically blocked avoidance to about 50% in low and intermediate doses, but the highest dose used blocked both avoidance and escape. 4. Chlorpromazine was potent in blocking the avoidance response, and nalorphine did not interfere with this action. Chlordiazepoxide had only a slight effect in blocking the avoidance response. 5. Interference with 5-hydroxytryptamine metabolism had no effect on the action of narcotics on conditioned avoidance; this finding is difficult to reconcile with the hypothesis that 5-hydroxytryptamine is involved in the analgesic action of morphine. 6. The results are consistent with the hypothesis that tranquillizer action is a necessary component of analgesia and may provide a basis for more complete screening of potential analgesics.

Tolerance to morphine-induced increases in [14C]catecholamine synthesis in mouse brain.

Morphine sulfate increased the incorporation of carbon-14-labeled tyrosine into labeled catecholamines in the mouse brain. Tolerance was manifested by a shift to the right in the dose-response curve for morphine after mice were treated repeatedly with morphine. Naloxone, a specific morphine antagonist, also shifted the dose-response curve for morphine to the right.