Showing papers on "Opiate published in 1988"

Itching after epidural and spinal opiates

Abstract: When opiates are administered by the epidural and spinal routes, itching occurs as a side effect. We reviewed 52 reports in the literature of the use of epidural and spinal opiates to assess the incidence of itching and found an overall incidence of 8.5% in patients receiving epidural opiates, and 46% in patients receiving spinal opiates. The symptom is a recognised, though rare, side effect of systemically administered opiates, and in the case of systemic administration the itching is generalised. In the case of epidural and spinal administration, the itching may be generalised. But often a segmental distribution is demonstrable, centred on the level of injection, or the itching is localised to a particular area such as the nose and face. It is likely therefore, in the latter case, that there is an effect upon the spinal cord itself. Although occasionally spinal opiate-induced itching is extremely troublesome and lessens the value of spinal opiate pain relief, in the majority of cases, the itching is not severe and is treatable with naloxone. However, the frequent occurrence of the symptom and the likelihood of a spinal cord mechanism do provide valuable information about opioid actions, and benefit may be derived from better understanding the phenomenon. This paper states a hypothesis to explain spinal opiate-induced itch and explores the possible mechanisms of the effect.

Perceived self-efficacy in coping with cognitive stressors and opioid activation.

Abstract: This experiment tested the hypothesis that perceived self-inefficacy in exercising control over cognitive stressors activates endogenous opioid systems. Subjects performed mathematical operations under conditions in which they could exercise full control over the cognitive task demands or in which the cognitive demands strained or exceeded their cognitive capabilities. Subjects with induced high perceived self-efficacy exhibited little stress, whereas those with induced low perceived self-efficacy experienced a high level of stress and autonomic arousal. Subjects were then administered either an inert saline solution or naloxone, an opiate antagonist that blocks the analgesic effects of endogenous opiates, whereupon their level of pain tolerance was measured. The self-efficacious nonstressed subjects gave no evidence of opioid activation. The self-inefficacious stressed subjects were able to withstand increasing amounts of pain stimulation under saline conditions. However, when endogenous opioid mechanisms that control pain were blocked by naloxone, the subjects were unable to bear much pain stimulation. This pattern of changes suggests that the stress-induced analgesia found under the saline condition was mediated by endogenous opioid mechanisms and counteracted by the opiate antagonist.

Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus.

Abstract: Acutely, morphine and D-ala2-D-leu-enkephalin (DADLE) inhibited adenylate cyclase in vitro in locus coeruleus (LC), dorsal raphe, frontal cortex and neostriatum and the inhibition by each agonist was blocked by the opiate-receptor antagonist naloxone. Although morphine was equally efficacious in the four brain regions examined (10-15% inhibition), DADLE inhibited cyclic AMP (cAMP) production to a greater extent in cortex and striatum (20-25% inhibition). Pertussis toxin treatment in vitro significantly reduced DADLE-inhibition of adenylate cyclase in all brain areas, indicating that this opiate response is mediated by a pertussis toxin-sensitive G-protein (i.e., Gi and/or Go). Chronic (in vivo) administration of morphine pellets for 5 days, treatment known to induce opiate tolerance and dependence, increased basal, GTP- and forskolin-stimulated adenylate cyclase in the LC, but not in the other three brain regions studied. DADLE was found to inhibit cAMP production in LC in vitro to the same extent in control and morphine-treated rats, suggesting a lack of opiate receptor tolerance. The morphine-induced increase in adenylate cyclase required chronic exposure to the opiate, as shorter treatment times, namely 2 hr and 1 day, failed to produce this effect. In fact, at 2 hr a small decrease in adenylate cyclase in the LC was observed that did not appear to be due to morphine being retained in the membrane fraction. Taken together, the findings of this study provide support for the view that changes in the cAMP system in the LC play a role in mediating acute opiate action as well as in underlying the development of opiate tolerance, dependence and/or withdrawal.

Chronic morphine treatment increases cyclic AMP-dependent protein kinase activity in the rat locus coeruleus.

Abstract: We have studied a possible role for cyclic AMP-dependent protein kinase in mediating opiate addiction in the central nervous system by focusing on the rat locus coeruleus. This brain region is well suited for these studies because it is relatively homogeneous and because a wealth of electrophysiological and behavioral data indicate that it plays an important role in mediating the chronic effects of opiates in animals, including humans. It was found that chronic, but not acute, in vivo treatment of rats with morphine increased cyclic AMP-dependent protein kinase activity in the locus coeruleus with a time course that closely paralleled the time course by which locus coeruleus neurons become tolerant to and dependent on opiates, based on electrophysiological studies. Concomitant administration of the opiate receptor antagonist naltrexone was found to block the effect of chronic morphine treatment on protein kinase activity, indicating that the effect is mediated via specific activation of opiate receptors. In contrast, chronic morphine treatment did not alter protein kinase activity in several other brain regions studied, including the neostriatum, frontal cortex, and dorsal raphe. We propose that the observed increase in cyclic AMP-dependent protein kinase activity in the locus coeruleus contributes to the biochemical basis of opiate addiction.

Multiple Morphine and Enkephalin Receptors and the Relief of Pain

Abstract: AFTER thousands of years, opiates remain the drugs of choice for severe pain. Their potency and ability to relieve the "hurt" associated with nociceptive stimuli without significantly altering such basic sensations as touch, temperature, and proprioception separate them from all other analgesics. Despite these advantages, side effects such as tolerance, physical dependence, respiratory depression, and constipation greatly limit their usefulness. In addition to these physiological actions of the opiates, their abuse is also a concern, but this remains uncommon in the treatment of acute pain and cancer pain. Opiates mimic the actions of a series of brain peptides and activate endogenous pain-modulating systems by binding to a number of different types of opioid receptors, each mediating distinct actions. Recent work indicates that the receptors responsible for many opiate side effects differ from those producing analgesia, implying that analgesics lacking these unwanted actions may be possible. This article reviews some physiological

Morphine and ibuprofen compared using the cold pressor test

Abstract: The analgesic efficacy of single doses of oral morphine sulphate solution (10 mg) and ibuprofen 600 mg was compared in 12 volunteers using a double-blind, double-dummy, placebo-controlled design on the cold pressor experimental pain model. Measurement of pain intensity was made before medication and then at 30, 60, 90, 120 and 180 min; blood samples were taken at these times for measurement of morphine and glucuronide metabolites by radioimmunoassay. Sessions were at least 5 days apart. Correlations were sought between analgesic effect and plasma concentrations of either morphine or morpnine-6-glucuronide. Morphine produced significant reduction in both peak pain intensity and area under the pain intensity curve compared with placebo; the threshold time was significantly increased by morphine compared with placebo. Ibuprofen was statistically indistinguishable from placebo on all three measures of analgesia. Analgesic effect and plasma concentrations of morphine showed significant correlation ( P = 0.053). The study confirmed reports of the opiate sensitivity of the cold pressor model, and the apparent insensitivity of the model to non-steroidal anti-inflammatory drugs.

Effect of Hyperglycemia on Pain Perception and on Efficacy of Morphine Analgesia in Rats

Abstract: The effect exerted by different hyperglycemic states on the pain threshold and on the analgesic potential of morphine was studied in male Sabra rats with the hot plate device. Hyperglycemia induced by an intraperitoneal injection of 0.014 mol/kg glucose or an acute or chronic diabetic state induced by streptozocin injection did not significantly alter the pain threshold. However, states of acute and chronic diabetes markedly blunted the analgesic effect of morphine (5 mg/kg). Sabra rats maintained on a cocktail of glucose-saccharin, thought to activate the release of endogenous opioids, demonstrated an increased pain threshold and rapidly developed resistance to the analgesic effect of morphine. Previous studies have shown that glucose in high concentration may interfere with the interaction of morphine on the opiate receptor. The influence of the diabetic state on beta-endorphin synthesis and concentration in the central nervous system is another factor that might change pain perception in diabetes. We propose that in diabetes, generally, the pain threshold is adequately maintained, despite the antagonistic effect of glucose, partly due to a compensatory increased secretion of endogenous opioid peptides. We hypothesize that in patients with chronic painful diabetic neuropathy, these normal analgesic response mechanisms may be overwhelmed either by an excess of nociceptive impulses from diseased peripheral nerves or conceivably by a failure of endogenous opioid secretory response to the hyperglycemia.

7 Action of opiates on gastrointestinal function

Abstract: Opioid peptides and opioid receptors are distributed along the gastrointestinal (GI) tract, indicating endogenous opiates released peripherally may modulate GI motor and secretory functions. Animal studies have revealed that the effects of opiates on gut motility depend on the nature of the subclasses of receptor involved, the species and the part of bowel. Most opiates that have a selective or predominant mu agonist activity inhibit gastric motility and delay gastric emptying by acting centrally; delta and kappa agonist are inactive when injected systemically. The effect of opiates in delaying intestinal transit observed in man, rat and other species is related to an inhibition (rat) or a stimulation (dog and man) of intestinal contractions as premature phase III-like sequences. The constipating effects of morphine probably result mainly from its action on colonic motility. Morphine stimulates colonic motility in humans by action on both central and peripheral sites. This increase in colonic motility and the delay in colonic transit is associated with a reinforcement of tonic contractions and reduced propulsive waves. Opioid peptides have been shown to participate in the colonic motor response to eating in man and animals. Both delta and mu receptors are involved in the stimulatory effects of opiates on colonic motility, while kappa receptors inhibit colonic contractions, mainly by acting centrally. The effects of opiates on gastric acid secretion are still controversial but it has been well demonstrated that opiates act centrally to reduce pancreatic secretion in rats. Opiates also inhibit intestinal secretions via an action on the enteric nervous system as well as in the CNS. All these results reinforce the hypothesis that opioid peptides have a major physiological role in the control of gut motility and secretions, and these actions explain most of the pharmacological effects of opiate substances on the digestive tract.

Brain stem neuronal circuitry underlying the antinociceptive action of opiates.

Abstract: Publisher Summary This chapter discusses the brain stem neuronal circuitry underlying the antinociceptive action of opiates. Opiates are the most potent and reliable analgesic agents. They are of great clinical value because their action on pain is selective: consciousness, motor function, and sensory function other than pain are spared at the usual analgesic doses. Opiates produce analgesia by an action at highly selective receptors located at specific anatomical sites within the central nervous system. The midbrain periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM) are brain stem components of a network that controls nociceptive transmission at the level of the spinal cord. Opiates injected at the brain stem elicit analgesia at doses that are orders of magnitude lower than those required to elicit an equianalgesic effect by systemic administration. Cutting the spinal dorsolateral funiculus, which contains descending projections from the RVM, reduces the effectiveness of a given dose of systemically administered morphine. Injection of the opiate antagonist naloxone into the RVM reverses the analgesic effect of systemically administered opiates. Thus, the RVM and PAG contribute to the analgesic effect of systemically administered opiates.

Spinal infusion of opiate and alpha-2 agonists in rats: tolerance and cross-tolerance studies.

Abstract: Intrathecal morphine or ST-91, an alpha-2 agonist, produce potent antinociception in a number of animal models. Using osmotic minipumps and a new Y-catheter technique, we show that chronic intrathecal (i.t.) infusion of morphine (2, 6 or 20 nmol/microliter/hr) or ST-91 (3, 10 or 30 nmol/microliter/hr) in rats produces a dose-dependent increase in hot-plate latency 1 day after pump implant. By 4 to 5 days after initiation of chronic infusion of either drug, hot-plate latencies do not differ from saline-infused controls. Rats rendered tolerant to one of the three chronic i.t. morphine doses (2, 6 or 20 nmol/microliter/hr) and tested at 7 days after initiation of infusion with a bolus i.t. dose of morphine, show a dose-dependent rightward shift in hot-plate dose-response curves. The two lower doses of chronic i.t. infusions of morphine produce parallel shifts of the subsequent i.t. administered morphine dose-response curves, but the highest chronic i.t. dose of morphine (20 nmol/microliter/hr) produces a significantly greater slope of the subsequent i.t. administered morphine dose-response curve. Animals exposed to chronic i.t. infusion of one of three doses of ST-91 (3, 10 or 30 nmol/microliter/hr) display a parallel, dose-dependent rightward shift to a subsequent bolus i.t. injection of ST-91. Rats rendered tolerant to chronic i.t. infusions of ST-91 showed no difference in the response to i.t. administered morphine hot-plate dose-response curves as compared to saline infused controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation of pentazocine analgesia by low-dose naloxone.

Abstract: The analgesia produced by combinations of low-dose naloxone with pentazocine or morphine was studied in 105 patients with moderately severe postoperative pain after standardized surgery for removal of impacted third molars. Pain intensity was quantified using a visual-analogue scale. To eliminate the release of endogenous opioids produced by the placebo component of open drug administration, all injections were made by a preprogrammed infusion pump. The analgesia produced by pentazocine, an agonist-antagonist opiate-analgesic acting predominantly at the kappa opiate receptor, was potentiated by low-dose naloxone, whereas the analgesia produced by morphine, a mu-agonist, was attenuated by low-dose naloxone. To evaluate whether similar potentiation would be present in an animal model, and specifically, in the absence of diazepam, which patients receive, we performed an analogous experiment in rats in which nociceptive threshold was determined using the Randall-Selitto paw-withdrawal test. The results were completely analogous to the clinical results: pentazocine analgesia was potentiated by low-dose naloxone, whereas morphine analgesia was attenuated by low-dose naloxone. These data demonstrate a novel interaction between opiates, and suggest a rationale for opiate combinations to produce potent analgesia with fewer autonomic side effects and less abuse potential than presently available analgesics.

Parity-associated reductions in behavioral sensitivity to opiates.

Abstract: Behavioral and physiological responses differ between primiparous and multiparous female rodents. Specifically, multiparous females respond with the full repertoire of maternal behaviors much more rapidly and with greater intensity than their primiparous counterparts. Since opiates inhibit the expression of maternal behavior in postpartum rats and can be reversed by means of the opiate antagonist naloxone, we investigated whether multiparous females would be resistant to the inhibitory effects of opiates on maternal behavior, relative to primiparous females. In Experiment 1 we evaluated the effects of a range of doses of morphine sulfate (MS; 0.625, 1.25, 2.5, 5.0, and 10.0 mg/kg or saline) on maternal behavior in primiparous females on Days 5-6 of lactation. The 5.0 and 10.0 mg/kg doses effectively disrupted maternal behavior, whereas the lower doses were ineffective or only marginally disruptive. In Experiment 2, age-matched female rats were timed-mated and tested for maternal behavior from Day 5 to 13 of lactation, after daily injections of the 5.0 mg/kg dose of MS. On Day 5 of lactation, this morphine treatment eliminated full maternal behavior in 87% of the primiparous animals, but only 37% of the multiparous animals were affected. By Day 10 of lactation, 100% of the multiparous females displayed full maternal behavior after MS treatment, whereas only 69% of primiparous females were responsive. In Experiment 3, analgesic responses were measured both in rats experiencing their initial or second pregnancy, and in postpartum, lactating rats after MS (5.0 mg/kg) administration. Using a tail-flick apparatus to measure analgesia, we found multigravid females to be significantly less analgesic prepartum than primigravid females, suggesting less sensitivity to endogenous opioids.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal stress alters morphine- and stress-induced analgesia in male and female rats.

Abstract: Prenatal stress affects the expression of many opioid-regulated behaviors in adulthood, e.g., aggressive, maternal, regulatory, and sexual. In the present report we examined two forms of analgesia, morphine-induced (opioid receptor-mediated), and stress-induced [cold-water swim (CWS), nonopioid] analgesia in adult prenatally-stressed (P-S) male and female rats to determine whether and to what extent these analgesic responses might be altered. Timed-mated Sprague-Dawley females were exposed to heat and restraint stress (three daily 1 2 hour sessions, 0830, 1230, and 1630 hr) from days 15–22 of gestation. Control animals remained undisturbed throughout pregnancy. Between 120–150 days of age, baseline pain sensitivities were determined using a tail-flick monitor. P-S and Control animals were then exposed to 3.5 min cold-water swims (2°C) and pain thresholds were again determined at 30 min intervals for 120 min. P-S females exhibited significantly lower pain thresholds than Control females at the 30 and 60 min marks, whereas P-S and Control males did not differ. Six to eight days later, analgesia was measured for 180 min following morphine (5.0 mg/kg) administration. P-S females exhibited significantly greater analgesia at each time-point after morphine treatment than Controls. Conversely, P-S males were significantly less analgesic than Control males from 60 to 180 min. These data suggest that prenatal stress alters the status of endogenous opiate systems. Such prenatal stress-induced alterations in opiate function may help account for some of the behavioral effects reported in P-S animals.

Endorphins, opiates, and behavioural processes

Abstract: Overview of the Endogenous Opioid Systems: Anatomical, Biochemical and Functional Issues Physiological Dependence on Opioids Opioid Reinforcement Processes Tolerance, Endorphins and Other Aspects of Opiate Drug Discrimination Environmentally-Induced Analgesia: Situational Factors, Mechanisms and Significance Endorphins, Opiates and Food Intake Evidence for Opioid Involvement in Controls of Drinking and Water Balance The Role of Opioid Mechanisms in Social Interaction and Attachment Endorphins and Sexual Behaviour Endorphins, Exploration and Activity Opioid Modulation of Learning and Memory Endogenous Opioid Systems and Neurobehavioral Development Neurochemical Methods in the Study of the Role of Endorphins in Psychiatric Disorders Narcotic Antogonist and Opioid Treatment in Psychiatry.

The use of opiate antagonists in treating bulimia: A study of low-dose versus high-dose naltrexone

Abstract: Sixteen individuals with bulimia consented to a 6-week trial of naltrexone, receiving either standard dosages of 50-100 mg each day or high dosages of 200-300 mg each day At the end of 6 weeks, individuals in the low-dose group had no significant change in their frequency of binge eating or purging, while individuals in the high-dose group had significant reductions in both behaviors Four individuals in the low-dose group who were crossed over to high-dose naltrexone at the end of the study went on to experience significant reductions in binge eating and purging These findings support the potential utility of opiate blockade in treating bulimia, but suggest that dosages of naltrexone greater than those needed to block exogenous opiates may be required for therapeutic efficacy in reducing binge eating and purging

Lack of an effect of 6-hydroxydopamine lesions of the nucleus accumbens on intravenous morphine self-administration.

Abstract: The neurotoxin, 6-hydroxydopamine (6-OHDA), has been used to selectively destroy dopamine containing neurons in discrete brain regions. Lesions of the nucleus accumbens with this neurotoxin decrease or eliminate cocaine and amphetamine self-administration and either increase or do not affect opiate self-administration in rats with unrestricted access to food and water. This study reports the effects of 6-OHDA lesions of the nucleus accumbens on responding maintained by food, water or morphine (3.3 mg/infusion). Six male rats with continuous access to three response levers were trained on a concurrent chained, fixed-ratio 1, fixed-ratio 9 schedule of reinforcer presentation. After stable patterns of responding were maintained by the three reinforcers, dose-effect curves for morphine were determined by substituting other doses of morphine or vehicle for 24-hour periods. Bilateral sham vehicle or 6-OHDA lesions of the nucleus accumbens were then completed and the effects of the lesion on food, water and morphine intake determined. Dose-effect evaluations were repeated after the lesion. The 6-OHDA lesions did not significantly affect responding maintained by food, water or morphine. The absence of an effect is most likely not the result of an insensitive baseline since other neurotoxin lesions produce long-term and selective decrements in morphine self-administration without affecting food and water responding. Like so many other manipulations, the magnitude of the effect that a neurotoxin lesion can exert on behavior may depend on the specific procedures that are used to maintain responding.

Stress-induced suppression of luteinizing hormone concentrations in wild baboons: role of opiates.

Abstract: Numerous stressors disrupt male reproductive physiology; previous studies of a population of wild baboons, living freely in a national park in East Africa, indicated that the stress of anesthetization by phencyclidine darting decreased both LH secretion and testicular sensitivity to LH. This study was undertaken to determine the mechanism(s) of the decreased LH secretion in these animals. Neither stress-induced glucocorticoid nor catecholamine release was responsible, since neither blockade of glucocorticoid secretion with the adrenal steroidogenesis inhibitor metyrapone nor blockade of catecholamine secretion with the sympathetic ganglionic blocking drug chlorisondamine prevented the stress-induced decline in serum LH concentrations. Administration of the opiate receptor antagonist naloxone (0.5 mg/kg BW), however, not only prevented the decline, but also transiently elevated serum LH concentrations, suggesting that opiates play a role in tonic as well as stress-induced decreases in LH secretion. Administration of a small dose of naloxone (0.03 mg/kg BW) commensurate with occupancy of only mu-opiate receptors slowed the stress-induced decline in LH concentrations, as did administration of the kappa-receptor antagonist MR 1452. These data suggest that opiates inhibit LH release via the combined occupancy of both mu- and kappa-receptors.

Opiate analysis in cadaveric blowfly larvae as an indicator of narcotic intoxication.

Abstract: Specimens of liver were collected from 40 cases in which the cause of death had been determined to be opiate intoxication. Rearings of Calliphora vicina larvae were then promoted on the decomposing liver. A control group of 10 decomposed liver specimens from non-opiate deaths was treated similarly. Analysis of larvae and liver for opiates (morphine) was conducted by radioimmunoassay. Good qualitative and quantitative correlation was observed in both the positive and negative groups. Regression analysis comparing the concentrations of opiates found in the larvae with those found in the liver in the positive group resulted in a correlation of r = 0.790.

Antagonist treatment in nucleus accumbers or periaqueductal grey affects heroin self-administration

Abstract: The role of opiate receptors in the periaqueductal grey and nucleus accumbers in maintenance of intravenous herion self-administration was examined by means of intracranial microinjections of the quaternary opiate antagonist methyl naltrexone. Over a dose range of 0–3.0 micrograms, pre-session infusions of methyl naltrexone in either brain site produced dose-related increases in responding for heroin (0.06 mg/kg/infusion) on a CRF schedule, without causing significant changes in responding on a second actvity control lever. Involvement of the periaqueductal grey was also examined in animals administering a lower heroin dose (0.03 mg/kg/infusion) in shorter sessions in order to minimize drug exposure prior to treatment. In this experiment, infusion of methyl naltrexone selective increases in responding for heroin, whereas treatment with the identical dose of methyl naltrexone had no effect on cocaine self-administration (1.0 mg/kg/infusion) in the same animals. With respect to the nucleus accumbens, these data confirm its involvement in opiate self-administration. Data for the periaqueductal grey provide the first evidence that opiate receptors in the vicinity of this brain region may play a role in intravenous opiate self-administration.

Treating opiate dependence

Abstract: A pharmaceutical composition in sublingual unit dosage form for maintenance treatment of opiate addicts comprising from 2 to 8 mg buprenorphine and an amount of naltrexone sufficient to substantially attenuate the euphorigenic effect of the buprenorphine when injected and to provide greater opiate blocking effect than that of naltrexone alone.

Contributions of taste factors and gender to opioid preference in C57BL and DBA mice.

Abstract: C57BL/6J and DBA/2J mouse strains have been characterized as morphine preferrers and avoiders, respectively (Horowitz et al. 1977). Previously, sweetened morphine solutions were presented with a water alternative, primarily with male subjects. Because sweetness may affect the endogenous opioid system and rodents have shown strain and sex differences in taste preferences, this study looked for strain- and gender-related taste preferences that might have affected opiate consumption. Preference for sweetened and unsweetened morphine and etonitazene was compared across gender and strain. In all choice tests, the control was a similar tasting quinine sulphate solution. Under these conditions, C57BL/6J mice continued to show strong preference for morphine. However, DBA/2J mice drank approximately equal amounts of morphine and quinine solutions, rather than avoiding morphine as when water was the alternative. Both strains appeared surprisingly indifferent to the synthetic opioid etonitazene, compared because it is potent at concentrations having barely perceptible bitterness. This raises the possibility of unexpected differences in post-ingestional effects between morphine and etonitazene. Contrary to reports of gender differences in sweet preference in rats, none were found in either strain of mouse. Neither were there any significant sex differences in opiate preference in either strain. C57 mice preferred sweetness more than did DBA mice.