u-50488 and Opioid-Related-Disorders

This laboratory perspective reviews the pharmagologic approaches that have been used in preclinical animal models to demonstrate the ability of competitive (LY274614) and noncompetitive (MK801 and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists to attenuate or reverse the development of morphine tolerance. We provide additional data to support previous observations that these NMDA antagonists modulate morphine (mu) opioid tolerance but do not affect U50488H (kappa 1) opioid tolerance. A strategy, which utilizes efficacy as an NMDA receptor antagonist and clinical safety, provides the basis for a discussion of the clinical potential of dextromethorphan, ketamine, and felbamate as modulators of opioid tolerance in pain patients or opioid addicts. The potential use of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors in neuropathic pain is also discussed.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Dextromethorphan; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Isoquinolines; Narcotics; Nitric Oxide Synthase; Opioid-Related Disorders; Pyrrolidines; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa; Receptors, Opioid, mu

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Humans; Mice; Mice, Inbred Strains; Opioid-Related Disorders; Pyrrolidines; Receptors, Opioid; Substance Withdrawal Syndrome

Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not markedly altered by concurrent treatment with THC. Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Opioid; Animals; Benzoxazines; Cannabinoid Receptor Agonists; Cyclohexanols; Dose-Response Relationship, Drug; Dronabinol; Drug Tolerance; Heart Rate; Macaca mulatta; Morphine; Morpholines; Naphthalenes; Opioid-Related Disorders; Pain Measurement; Substance Withdrawal Syndrome

Pruritus is a common adverse effect of opioid treatment. However, the mechanism by which pruritus is induced by opioid administration is unclear. In this study, we examined the effects of the intradermal injection of loperamide, a peripherally restricted opioid receptor agonist, on the itch sensation. When injected intradermally into the rostral part of the back in mice, loperamide elicited scratching behavior. We also examined the effects of the selective mu opioid receptor agonist [d-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin acetate (DAMGO), the selective delta opioid receptor agonist [d-Pen(2,5)]-enkephalin (DPDPE), and the selective kappa opioid receptor agonist U-50488H on scratching behavior in mice in order to determine which subtype is involved in opioid-induced pruritus. Following intradermal injection into the rostral part of the back in mice, DAMGO elicited scratching behavior, while DPDPE and U-50488H did not. This suggests that peripheral mu opioid activation elicits the itch sensation. Next, we focused on the treatment of opioid-induced itch sensation without central adverse effects. Naloxone methiodide is a peripherally restricted opioid receptor antagonist. In the present study, naloxone methiodide significantly suppressed scratching behavior induced by loperamide and DAMGO. These findings suggest that mu opioid receptors play a primary role in peripheral pruritus and that naloxone methiodide may represent a possible remedy for opioid-induced itching.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Antipruritics; Behavior, Animal; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Injections, Intradermal; Loperamide; Male; Mice; Mice, Inbred ICR; Naloxone; Opioid-Related Disorders; Pruritus; Quaternary Ammonium Compounds; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Skin

Although mu-opioids such as morphine are undoubtedly effective in the treatment of acute and postoperative pain, kappa-opioids are of interest for the modulation of visceral pain. In the present study, we compared a kappa-opioid agonist (U50488-H; 0.63-40 mg/kg) with a mu-opioid agonist (morphine; 0.63-40 mg/kg) in different pain models (tail withdrawal, writhing, formalin and plantar test) to represent acute, peritoneovisceral and inflammatory pain states in rats. The effects of the respective receptor agonists on gastrointestinal motility, muscle rigidity and abuse liability were also studied in appropriate animal models (charcoal, castor oil, rotarod and drug discrimination learning). Morphine was highly efficacious in all the nociceptive models employed, but also elicited a potent inhibition of gastric motility, caused severe muscle rigidity and locomotor disturbances and displayed a potential for abuse liability at the higher doses tested (> or =10 mg/kg morphine). In contrast, U50488-H was inactive in the tail withdrawal test, but was more effective in visceral and inflammatory pain settings. Although U50488-H did not elicit any gastrointestinal inhibition, a loss of muscle tone following administration of the compound led to detrimental effects on rotarod performance. The findings presented here indicate that kappa-opioids possess antinociceptive efficacy in visceral and inflammatory pain settings, but their administration can lead to a loss of muscle tone. In contrast, mu-opioids are highly active as analgesics against a range of nociceptive stimuli, but also concomitantly elicit strongly adverse effects.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Gastrointestinal Motility; Male; Morphine; Muscle Rigidity; Opioid-Related Disorders; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu

We have comparatively studied the effects of two opioids in the rat place conditioning paradigm in identical experimental conditions (including double drug/saline conditioning daily sessions for 3 days), with the only exception of using either a two- or three-conditioning compartment apparatus. Morphine-induced place preference appeared to be similar with two- and three-conditioning compartments, but U-50,488-induced place aversion was consistently more prominent when a two-conditioning compartment apparatus was used. It is suggested that, when the results of conditioning are being tested, the presence of neutral environments decreases the sensitivity of the procedure to quantify place aversions.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Association Learning; Avoidance Learning; Conditioning, Classical; Male; Mental Recall; Morphine; Motivation; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Reward; Social Environment

The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The CRF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF1) and CRF2. Here we report that genetic disruption of CRF1 receptor pathways in mice eliminates the negative affective states of opiate withdrawal. In particular, neither CRF1 receptor heterozygous (CRF1+/-) nor homozygous (CRF1-/-) null mutant mice avoided environmental cues repeatedly paired with the early phase of opiate withdrawal. These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H. We also examined the impact of CRF1 receptor-deficiency upon opiate withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular mechanism thought to underlie the negative affective states of drug withdrawal. Consistent with the behavioral indices, we found that, during the early phase of opiate withdrawal, neither CRF1+/- nor CRF1-/- showed increased dynorphin mRNA levels in the nucleus accumbens. This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Dynorphins; Female; Gene Expression Regulation; Mice; Mice, Knockout; Nucleus Accumbens; Opioid-Related Disorders; Receptors, Corticotropin-Releasing Hormone; Receptors, Opioid, kappa; RNA, Messenger; Signal Transduction; Substance Withdrawal Syndrome

Planarians (Dugesia dorotocephala) that were exposed for 1 h to cocaine (80 microM) or to the kappa-selective opioid receptor agonist U-50,488H (1 microM) displayed an abstinence-induced withdrawal syndrome, indicative of the development of physical dependence, when they were tested in cocaine- (or U-50,488H-) free water, but not when they were tested in cocaine- (or U-50,488H-) containing water. The withdrawal was manifested as a significant (P<0.05) decrease in the rate of planarian spontaneous locomotor activity over a 5-min observation period, using a recently designed metric. Co-exposure of the planarians to D-glucose (1 microM) or to 2-deoxy-D-glucose (2-DG, 1 microM), but not to L-glucose (1 microM), significantly attenuated (P<0.05) the development of physical dependence, shown by an attenuated withdrawal syndrome, from cocaine and U-50,488H. These results suggest that either D-glucose and 2-deoxy-D-glucose compete with a common cocaine and kappa-opioid transport mechanism or that the development of physical dependence (or the inhibition of abstinence-induced withdrawal) in planarians requires energy supplied from glucose metabolism.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adaptation, Physiological; Animals; Behavior, Addictive; Carbohydrate Conformation; Cocaine; Disease Models, Animal; Glucose; Narcotic Antagonists; Opioid-Related Disorders; Planarians; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

Many drug-abusers engage in poly-drug abuse, but there has been relatively little quantification of withdrawal from poly-drug use. Planarians are an advantageous model for these studies due to mammalian-relevant neurotransmitter systems (e.g. dopamine, opioid, and 5-HT). We recently developed a metric that quantified an acute cocaine withdrawal phenomenon in planarians. However, despite much indirect evidence, we lacked direct evidence of a receptor- or carrier-mediated effect. We now report dose-related, naloxone- and nor-binaltorphine-sensitive acute abstinence-induced withdrawal and naloxone-precipitated withdrawal from the kappa-opioid agonist U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)-benzeneacetamide). The less active enantiomer [1R,2R]U-50,488 produced significantly less withdrawal and U-50,488H withdrawal was not due to pH or osmolarity. These data provide pharmacologic evidence of a kappa-opioid receptor-mediated withdrawal phenomenon and neuroadaptation to a pharmacologic stimulus (adaptations in transduction mechanisms) in this model.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adaptation, Physiological; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Osmolar Concentration; Planarians; Reaction Time; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

Topics: Animals; Aorta, Thoracic; Cocaine; Cyclic AMP; Electric Stimulation; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Mice; Muscle, Smooth; Opioid-Related Disorders; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Serotonin; Substance-Related Disorders

Nalbuphine, an opioid mixed agonist-antagonist, prevents many morphine-related side effects. In this study, we compared the effects of nalbuphine versus naloxone on the prevention of morphine tolerance and dependence in Sprague-Dawley rats. Group 1 received a morphine 5 mg/kg intraperitoneal (I.P.) injection. Groups 2 and 3 received single doses of nalbuphine (0.01 to 5 mg/kg I.P.) or naloxone (1 to 500 microg/kg I.P.) coadministered with morphine (5 mg/kg I.P.), respectively. Group 4 received a saline I.P. injection. Treatments were continued for 4 days. The occurrence of tolerance was estimated by comparing the antinociceptive effect of morphine on Day 1 (Group 1) and Day 5 (each group). The severity of dependence was determined by precipitated withdrawal signs (incidence of diarrhea and teeth chattering) induced by naloxone (10 mg/kg I.P.). We found that coadministration of nalbuphine or naloxone with morphine dose-dependently blocked the development of morphine tolerance and dependence. However, unlike naloxone, nalbuphine did not attenuate the antinociceptive effect of morphine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Tolerance; Male; Morphine; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Pyrrolidines; Rats; Rats, Sprague-Dawley

The effect of dexamethasone on acute opiate withdrawal induced by mu, kappa and delta receptor agonists was investigated in vitro. After a 4-min in vitro exposure to morphine (less selective mu agonist), D-Ala2-N-methyl-Phe4-Gly5-ol)-enkephalin (DAGO; highly selective mu agonist) and trans(+/-)-3,4-dichloro-N-methyl-N-[2(1-pyrrolidynyl)cyclohexyl]- benzeneacetamide (U50-488H; highly selective kappa agonist) a strong contracture of guinea pig isolated ileum was observed after the addition of naloxone. This effect was also observed when rabbit isolated jejunum was pretreated with deltorphin (highly selective delta agonist). Dexamethasone treatment before or after the opioid agonists tested was capable of both preventing and reverting the naloxone-induced contracture after exposure to mu opiate agonists morphine and DAGO in a concentration- and time-dependent fashion. Also, the steroid reduced naloxone-induced contracture after the exposure to U50-488H only when injected before the kappa opiate agonist. Finally, it did not affect the naloxone contracture after exposure to deltorphin. Pretreatment with RU-38486, a glucocorticoid receptor antagonist, inhibited dexamethasone antagonism on responses to both mu and kappa agonists, whereas pretreatment with cycloheximide, a protein synthesis inhibitor, blocked only the antagonistic effects of dexamethasone on responses to the mu opioid agonists. Overall, these data indicate that dexamethasone induces significant effects on mu-mediated opiate with-drawal in vitro, which suggest an important functional interaction between corticosteroids and the opioid system primarily at the mu receptor level. The ability of RU-38486 and cycloheximide to block dexamethasone effects indicates that the steroid interference on mu-mediated withdrawal involves a protein synthesis-dependent mechanism via glucocorticoid receptor.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cycloheximide; Dexamethasone; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Guinea Pigs; In Vitro Techniques; Male; Mifepristone; Muscle Contraction; Naloxone; Opioid-Related Disorders; Pyrrolidines; Rabbits; Substance Withdrawal Syndrome

We have previously reported that chicken embryos injected with a single dose of methadone (Meth) on day 3, 7 or 11 of embryogenesis fail to show dependence on day 14, measured as a significant overshoot in motility above baseline after challenge with the opioid antagonist naloxone (Nx). Constant infusion of Meth from day 7 to 14 also failed to produce evidence of dependence on day 14. To address the question of whether the 14-day-old embryo is capable of expressing withdrawal, isobutylmethylxanthine (IBMX), a compound that produces quasi-opioid withdrawal, was injected directly into the embryo, resulting in a significant increase in motility. To determine whether the 14-day-old embryo could also express true opioid withdrawal, the embryos were injected with various doses of Meth or morphine (Morph), followed at different time intervals by injections of varying doses of Nx. A high dose of Morph followed 24 hours later by a low dose of Nx produced evidence of withdrawal, as did a low dose of Meth followed 1 hour later by a higher dose of Nx, U50488H, a selective kappa agonist, had no effect on motility in the 14-day-old embryo, suggesting that the decrease in motility seen after Meth was not mediated by a kappa receptor. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine (B-FNA), blocked the decrease in motility seen after Meth and also prevented the overshoot in motility when Nx was given 1 hour post-Meth. We were also able to demonstrate dependence/withdrawal in the 12-day-old embryo, but higher doses of both Meth and Nx were required.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-3-isobutylxanthine; 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Chick Embryo; Methadone; Morphine Dependence; Motor Activity; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Pyrrolidines; Receptors, Opioid; Substance Withdrawal Syndrome