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S Stevens Negus - One of the best experts on this subject based on the ideXlab platform.

  • Modulation of drug choice by extended drug access and withdrawal in rhesus monkeys: Implications for negative reinforcement as a driver of addiction and target for medications development.
    Pharmacology biochemistry and behavior, 2017
    Co-Authors: S Stevens Negus, Matthew L Banks
    Abstract:

    Chronic drug exposure is hypothesized to recruit negative reinforcement processes that increase the magnitude and alter the mechanisms of drug reinforcement. Candidate substrates of negative reinforcement include increased signaling via stress-related neurotransmitters such as corticotropin releasing factor (CRF, acting at CRF receptors) or dynorphin (acting at kappa opioid receptors) and/or decreased signaling via reward-related neurotransmitters such as dopamine. Determinants of drug reinforcement can be examined with choice procedures, in which subjects choose between a drug of interest (e.g. heroin or cocaine) and a non-drug alternative reinforcer (e.g. food). This review summarizes evidence collected from studies of drug choice in rhesus monkeys to address the negative reinforcement hypothesis. In monkeys choosing between heroin and food, chronic heroin exposure and subsequent withdrawal produces a robust increase in heroin choice. This withdrawal-associated increase in heroin choice is blocked by morphine and by other mu opioid Agonists used to treat opioid use disorder (methadone, buprenorphine); however, withdrawal-associated increases in heroin choice are not reliably blocked by antAgonists of CRF or kappa opioid receptors or by an indirect dopamine agonist. In monkeys choosing between cocaine and food, chronic cocaine exposure and withdrawal fail to increase cocaine choice or alter sensitivity of cocaine choice to treatment with candidate therapeutics including an indirect dopamine agonist and a kappa opioid receptor antagonist. These results support a role for negative reinforcement in self-administration of heroin but not cocaine. The constellation of neurobiological changes that constitutes the negative reinforcing stimulus in opioid-dependent rhesus monkeys remains to be determined.

  • Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys
    Pain Research and Treatment, 2012
    Co-Authors: S Stevens Negus, Ember M. Morrissey, John E. Folk, Kenner C Rice
    Abstract:

    Delta opioid Agonists enhance antinociceptive effects of Mu-Opioid Agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu Agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine). Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg). SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu Agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

  • Effects of the delta-opioid agonist SNC80 on the abuse liability of methadone in rhesus monkeys: a behavioral economic analysis.
    Psychopharmacology, 2011
    Co-Authors: Matthew L Banks, Kenner C Rice, John E. Folk, Peter G. Roma, S Stevens Negus
    Abstract:

    Rationale Delta-opioid Agonists enhance the antinociceptive efficacy of methadone and other Mu-Opioid Agonists. However, relatively little is known about the degree to which delta Agonists might enhance the abuse-related effects of mu Agonists.

  • Antinociceptive interactions between Mu-Opioid receptor Agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy.
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: Matthew L Banks, Kenner C Rice, S Stevens Negus
    Abstract:

    Mu-Opioid Agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu Agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu Agonists with varying efficacy at mu receptors (nalbuphine morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu Agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

  • Effects of Mu Opioid Agonists Alone and in Combination with Cocaine and D-Amphetamine in Rhesus Monkeys Trained to Discriminate Cocaine
    Neuropsychopharmacology, 1998
    Co-Authors: S Stevens Negus, Michael B Gatch, Nancy K Mello
    Abstract:

    Psychomotor stimulants and mu opioid Agonists are often used together by polydrug abusers, and it has been suggested that this form of polydrug abuse may result from the ability of stimulants and mu Agonists to enhance each other's abuse-related effects. To investigate this possibility, the present study examined stimulant-opioid interactions in rhesus monkeys trained to discriminate cocaine. Specifically, the effects of the mu opioid Agonists heroin, alfentanil, fentanyl, and morphine administered alone or in combination with cocaine or d-amphetamine were examined in five monkeys trained to discriminate 0.4 mg/kg cocaine (IM) from saline in a two-lever, food-reinforced drug discrimination procedure. When administered alone, the rapid onset mu Agonists heroin (0.032–0.32 mg/kg) and alfentanil (0.01–0.1 mg/kg) substituted completely for cocaine in three of five monkeys but produced primarily saline-appropriate responding in the other two monkeys. The slower onset mu Agonists fentanyl (0.0056–0.056 mg/kg) and morphine (0.56–10 mg/kg) substituted for cocaine in only one of five monkeys. When administered as pretreatments to cocaine, morphine and fentanyl increased levels of cocaine-appropriate responding produced by low doses of cocaine in some monkeys. Morphine pretreatment also increased levels of cocaine-appropriate responding produced by low doses of amphetamine in some monkeys. However, in other monkeys, morphine and fentanyl pretreatment did not alter the discriminative stimulus effects of cocaine or amphetamine. These results indicate that there are substantial individual difference in the effects of mu Agonists in cocaine-discriminating rhesus monkeys. In some monkeys, mu Agonists mimic or enhance the discriminative stimulus of cocaine, whereas in other monkeys, mu Agonists neither mimic nor enhance the effects of stimulants.

Stephen G. Holtzman - One of the best experts on this subject based on the ideXlab platform.

  • Modulation of the Discriminative Stimulus Effects of d-Amphetamine by Mu and Kappa Opioids in Squirrel Monkeys
    Pharmacology Biochemistry and Behavior, 2000
    Co-Authors: Kelly R Powell, Stephen G. Holtzman, Stephen G. Holtzman
    Abstract:

    It has been reported that the discriminative stimulus effects of cocaine in squirrel monkeys can be potentiated by mu opioid Agonists and attenuated by kappa opioid Agonists. The purpose of this study was to extend these observations by examining the effects of mu and kappa opioids Agonists on the discriminative stimulus effects of d-amphetamine (AMPH). Five squirrel monkeys were trained to discriminate 0.3 mg/kg of AMPH (i.m.) from saline using a stimulus termination/avoidance task. AMPH and cocaine substituted dose dependently for the AMPH training stimulus in all five monkeys. The AMPH training dose was completely antagonized by 0.1 mg/kg of the D1 dopamine antagonist SCH 39166. When administered alone, the kappa agonist U69,593 substituted partially or completely for AMPH in four of five monkeys, the kappa agonist enadoline substituted completely for AMPH in two of five monkeys, and morphine substituted completely for AMPH in one monkey. In all five monkeys, pretreatment with some doses of U69,593 or enadoline attenuated the discriminative stimulus effects of AMPH; however, some doses of U69,593 and enadoline also potentiated the effects of AMPH in at least two monkeys. Morphine pretreatment potentiated the discriminative stimulus effects of AMPH in three monkeys and either attenuated or did not alter these effects in two monkeys. Morphine pretreatment did not significantly alter the discriminative stimulus effects of cocaine except in one monkey. These data indicate large individual differences in the abilities of mu and kappa opioid Agonists to alter the discriminative stimulus effects of AMPH.

  • Mu Opioid Agonists Potentiate Amphetamine- and Cocaine-Induced Rotational Behavior in the Rat
    The Journal of pharmacology and experimental therapeutics, 1997
    Co-Authors: Heather L. Kimmel, Stephen G. Holtzman
    Abstract:

    Opioids modulate brain dopaminergic function in various experimental paradigms. This study used the rotational model of behavior in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway to investigate this interaction. Doses of two presynaptically acting dopaminergic drugs, amphetamine and cocaine, were coadministered with several doses of the mu opioid agonist, morphine. Morphine, at 3.0 mg/kg, potentiated rotational behavior induced by each dose of the stimulants. To determine the receptor specificity of the actions of morphine, the mu opioid Agonists buprenorphine, fentanyl, levorphanol, meperidine, and methadone, and dextrorphan, the non-opioid isomer of levorphanol, were administered alone and with 1.0 mg/kg amphetamine. Each of these drugs, as well as morphine, produced circling behavior on its own. All of the mu opioid Agonists and dextrorphan increased amphetamine-induced turning; the coadministration of dextrorphan, levorphanol, meperidine, methadone and morphine with amphetamine produced turning greater than predicted by simple additivity. To determine whether an opioid receptor was involved in these interactions, the opioid antagonist, naltrexone, was administered before the amphetamine/mu opioid receptor agonist combination. Naltrexone blocked the potentiating effects of morphine, but not those of the other drugs. Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor Agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role of mu opioid receptors in these effects remains unclear.

  • Intracranial self-stimulation in rats: sensitization to an opioid antagonist following acute or chronic treatment with mu opioid Agonists.
    The Journal of pharmacology and experimental therapeutics, 1997
    Co-Authors: Keith W Easterling, Stephen G. Holtzman
    Abstract:

    Acute mu opioid agonist pretreatment (4 hr) dose-dependently sensitizes rats responding for food reinforcement to the rate-decreasing effects of naltrexone (NTX). In the present study, adult rats were trained to respond in an intracranial self-stimulation autotitration procedure in which responding resulted in electrical stimulation of the medial forebrain bundle that decreased in frequency until reset to the initial value. In an acute sensitization experiment, pretreatment (4 hr) doses of 3.0 and 10 mg/kg morphine reduced the ED25 value for the intracranial self-stimulation rate-decreasing effect of NTX from 28.2 mg/kg to 0.29 and 0.02 mg/kg, respectively. All mu -selective opioid Agonists tested, fentanyl > levorphanol > methadone > morphine > meperidine (listed in order of decreasing potency), produced similar large increases in sensitivity to NTX. Acute sensitization was not induced by the kappa -selective opioid agonist spiradoline, the dextrorotary enantiomer of levorphanol, dextrorphan, or the nonopioid drugs d -amphetamine and pentobarbital. Pretreatment with morphine for 10 days by continuous subcutaneous infusion (15 mg/kg/day) reduced the ED25 value of NTX from 28.2 to 0.002 ± 1.48 mg/kg. The correlation of decreases in ED25 values for the rate-decreasing effect of NTX after both acute and chronic morphine administration is consistent with the theory that acute agonist-induced sensitization reflects receptor-mediated changes occurring early in the development of physical dependence.

  • Discriminative stimulus effects of dextromethorphan in the rat
    Psychopharmacology, 1994
    Co-Authors: Stephen G. Holtzman
    Abstract:

    This study was performed to characterize pharmacologically the discriminative stimulus effects of dextromethorphan, an antitussive that binds with high affinity to a subtype of sigma site in the brain. Dextrorphan, a metabolite of dextromethorphan, has phencyclidine (PCP)-like effects. Therefore, training was conducted with dextromethorphan injected by the SC route, which minimizes dextrorphan formation compared to the IP route. The training dose used, 30 mg/kg, by the SC route did not occasion selection of the PCP-appropriate choice lever in rats discriminating IP injections of 2.0 mg/kg PCP from saline. (In contrast, by the IP route the ED_50 of dextromethorphan for PCP-appropriate lever selection was 21.7 mg/kg). In rats discriminating 30 mg/kg (SC) of dextromethorphan from distilled water, dextromethorphan was slightly more potent SC than it was IP (ED_50s for dextromethorphan-appropriate lever selection: 8.5 and 14.9 mg/kg, respectively). These animals generalized dose-dependently and completely to PCP and to other PCP-receptor ligands, but selected the vehicle-appropriate choice lever when tested with sigma -site ligands, mu -opioid Agonists, and naltrexone. Concurrent administration of naltrexone or sigma -site ligands with 30 mg/kg dextromethorphan did not block dextromethorphan-appropriate responding. These results show that the discriminative effects of SC dextromethorphan are PCP-like and are not mediated by the high-affinity dextromethorphan binding site or by the mu -opioid receptor. Because little dextrorphan is formed when dextromethorphan is given SC and because dextromethorphan itself has low affinity for the PCP receptor, the discriminative effects of SC dextromethorphan probably are mediated by a recognition site related closely to but different from the PCP receptor.

  • Sensitization and tolerance to the discriminative stimulus effects of Mu-Opioid Agonists
    Psychopharmacology, 1994
    Co-Authors: Carol A. Paronis, Stephen G. Holtzman, Stephen G. Holtzman
    Abstract:

    The discriminative stimulus effects of several μ-opioid Agonists were examined under conditions of opioid sensitization or tolerance, i.e., before and after 1-week SC infusions of naloxone or μ-opioid Agonists. Rats were trained to discriminate 3.0 mg/kg morphine from saline using a two-lever, discrete trial, shock-avoidance/escape procedure. The rats generalized completely to morphine, fentanyl, meperidine, buprenorphine, and etorphine, and partially to pentazocine. A 7-day infusion of naloxone (0.3 mg/kg per h) potentiated the discriminative stimulus effects of all of these drugs. The magnitude of the increased potency varied indirectly with the efficacy of the μ-opioid Agonists; potency ratios (pre-infusion ED50/post-infusion ED50) ranged from 1.58 (etorphine) to 3.58 (pentazocine). Stimulus generalization to morphine, fentanyl, and meperidine also was examined following infusions of equieffective doses of each of these three drugs. Differences among drugs were generally small, and failed to reach statistical significance. Nonetheless, the induction of μ-opioid tolerance did seem to vary with the efficacy of the three μ-opioid Agonists. Thus, meperidine (6.25 mg/kg per h), which has the lowest efficacy of the drugs infused, produced the greatest shift to the right of the stimulus-generalization curves of these three drugs; the post-meperidine PR ranged between 0.40 and 0.61. Fentanyl (0.1 mg/kg per h), a drug with a higher efficacy at μ-opioid receptors, did not produce tolerance to the discriminative stimulus effects of morphine, fentanyl, or meperidine; potency ratios ranged from 0.50 to 0.75. Potency ratios for buprenorphine, etorphine, fentanyl, meperidine, and morphine after 7-day morphine infusions (0.75 mg/kg per h) ranged from 0.38 (buprenorphine) to 0.80 (etorphine). Morphine induced significant tolerance only to the discriminative stimulus effects of fentanyl. Our results suggest that different cellular mechanisms underlie the development of tolerance and sensitization to the discriminative stimulus effects of μ-opioid Agonists.

Howard L. Fields - One of the best experts on this subject based on the ideXlab platform.

Matthew L Banks - One of the best experts on this subject based on the ideXlab platform.

  • role of mu opioid agonist efficacy on antinociceptive interactions between mu Agonists and the nociceptin opioid peptide agonist ro 64 6198 in rhesus monkeys
    European Journal of Pharmacology, 2019
    Co-Authors: Jeremy C. Cornelissen, Kenner C Rice, Floyd F. Steele, Rebekah D Tenney, Samuel Obeng, Yan Zhang, Matthew L Banks
    Abstract:

    Abstract Mu-Opioid receptor Agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP Agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of Mu-Opioid Agonists. The present study determined behavioral interactions between the NOP agonist (−)-Ro 64-6198 and Mu-Opioid ligands that vary in Mu-Opioid receptor efficacy (17-cyclopropylmethyl-3,14β-dihyroxy-4,5α-epoxy-6α-[(3 -isoquinolyl)acetamindo]morphinan (NAQ)

  • Additive and subadditive antiallodynic interactions between μ-opioid Agonists and N-methyl D-aspartate antAgonists in male rhesus monkeys
    Behavioural Pharmacology, 2018
    Co-Authors: Jeremy C. Cornelissen, Kenner C Rice, Floyd F. Steele, Katherine L. Nicholson, Matthew L Banks
    Abstract:

    Mu-Opioid Agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception, and N-Methyl D-Aspartate (NMDA) receptor antAgonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate undesirable effects of Mu-Opioid Agonists. Whether NMDA antAgonists enhance the antiallodynic effects of mu Agonists in preclinical models of thermal hypersensitivity (i.e. capsaicin-induced thermal allodynia) are unknown. The present study determined the behavioral effects of racemic ketamine, (+)-MK-801, (–)-nalbuphine, and (–)-oxycodone alone and in fixed-proportion mixtures in assays of capsaicin-induced thermal allodynia and schedule-controlled responding in rhesus monkeys. Ketamine, nalbuphine and oxycodone produced dose-dependent antiallodynia. MK-801 was inactive up to doses that produced undesirable effects. Ketamine, but not MK-801, enhanced the potency of mu Agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or sub-additive depending upon the mixture. Furthermore, oxycodone and MK-801 interactions were sub-additive on anti-allodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antAgonists as adjuncts to Mu-Opioid Agonists for thermal allodynic pain states.

  • Modulation of drug choice by extended drug access and withdrawal in rhesus monkeys: Implications for negative reinforcement as a driver of addiction and target for medications development.
    Pharmacology biochemistry and behavior, 2017
    Co-Authors: S Stevens Negus, Matthew L Banks
    Abstract:

    Chronic drug exposure is hypothesized to recruit negative reinforcement processes that increase the magnitude and alter the mechanisms of drug reinforcement. Candidate substrates of negative reinforcement include increased signaling via stress-related neurotransmitters such as corticotropin releasing factor (CRF, acting at CRF receptors) or dynorphin (acting at kappa opioid receptors) and/or decreased signaling via reward-related neurotransmitters such as dopamine. Determinants of drug reinforcement can be examined with choice procedures, in which subjects choose between a drug of interest (e.g. heroin or cocaine) and a non-drug alternative reinforcer (e.g. food). This review summarizes evidence collected from studies of drug choice in rhesus monkeys to address the negative reinforcement hypothesis. In monkeys choosing between heroin and food, chronic heroin exposure and subsequent withdrawal produces a robust increase in heroin choice. This withdrawal-associated increase in heroin choice is blocked by morphine and by other mu opioid Agonists used to treat opioid use disorder (methadone, buprenorphine); however, withdrawal-associated increases in heroin choice are not reliably blocked by antAgonists of CRF or kappa opioid receptors or by an indirect dopamine agonist. In monkeys choosing between cocaine and food, chronic cocaine exposure and withdrawal fail to increase cocaine choice or alter sensitivity of cocaine choice to treatment with candidate therapeutics including an indirect dopamine agonist and a kappa opioid receptor antagonist. These results support a role for negative reinforcement in self-administration of heroin but not cocaine. The constellation of neurobiological changes that constitutes the negative reinforcing stimulus in opioid-dependent rhesus monkeys remains to be determined.

  • Effects of the delta-opioid agonist SNC80 on the abuse liability of methadone in rhesus monkeys: a behavioral economic analysis.
    Psychopharmacology, 2011
    Co-Authors: Matthew L Banks, Kenner C Rice, John E. Folk, Peter G. Roma, S Stevens Negus
    Abstract:

    Rationale Delta-opioid Agonists enhance the antinociceptive efficacy of methadone and other Mu-Opioid Agonists. However, relatively little is known about the degree to which delta Agonists might enhance the abuse-related effects of mu Agonists.

  • Antinociceptive interactions between Mu-Opioid receptor Agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy.
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: Matthew L Banks, Kenner C Rice, S Stevens Negus
    Abstract:

    Mu-Opioid Agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu Agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu Agonists with varying efficacy at mu receptors (nalbuphine morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu Agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

James H. Woods - One of the best experts on this subject based on the ideXlab platform.

  • THE ROLE OF PERIPHERAL MU OPIOID RECEPTORS IN THE MODULATION OF CAPSAICIN-INDUCED THERMAL NOCICEPTION IN RHESUS MONKEYS
    The Journal of pharmacology and experimental therapeutics, 1998
    Co-Authors: Eduardo R. Butelman, James H. Woods
    Abstract:

    Capsaicin produces burning pain, followed by nociceptive responses, such as allodynia and hyperalgesia in humans and rodents. In the present study, when administered subcutaneously into the tail of rhesus monkeys, capsaicin (0.01–0.32 mg) dose-dependently produced thermal allodynia manifested as reduced tail-withdrawal latencies in 46°C water, from a maximum value of 20 sec to approximately 2 sec. Coadministration of selective mu opioid Agonists, fentanyl (0.003–0.1 mg) and (d-Ala2,N-Me-Phe4, Gly5-ol)-enkephalin (0.001–0.03 mg), dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by small doses of opioid antAgonists, quadazocine (0.03 mg) and quaternary naltrexone (1 mg), applied locally in the tail. However, these doses of antAgonists injected s.c. in the back did not antagonize local fentanyl. Comparing the relative potency of either agonist or antagonist after local and systemic administration confirmed that the site of action of locally applied mu opioid Agonists is in the tail. These results provide evidence that activation of peripheral mu opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model could be a useful tool for evaluating peripherally acting antinociceptive agents without central side effects and enhance new approaches to the treatment of inflammatory pain.

  • Discriminative stimulus effects of a centrally administered, delta-opioid peptide (d-Pen2-d-Pen5-enkephalin) in pigeons
    Psychopharmacology, 1996
    Co-Authors: David C. Jewett, Henry I Mosberg, James H. Woods
    Abstract:

    The present study assessed the discriminative stimulus effects of the delta-opioid agonist [d-Pen2-d-Pen5]enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injections of 100 µg [d-Pen2-d-Pen5]enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of discriminative control was rapid (14–28 daily sessions). [d-Ser2, Leu5, Thr6]enkephalin (DSLET) and [d-Ala2]deltorphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (0.032–100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01–1 mg/kg, IM), and the Mu-Opioid Agonists, DAMGO (0.1–3.2 µg, ICV) and morphine (1–10 mg/kg, IM), did not produce discriminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Naltrindole (0.1 mg/kg, IM), an antagonist selective for deltaopioid receptors, produced approximately a 30-fold reduction in the potency of DPDPE. DPDPE's discriminative stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo.

  • Discriminative stimulus effects of a centrally administered, delta-opioid peptide (d-Pen^2-d-Pen^5-enkephalin) in pigeons
    Psychopharmacology, 1996
    Co-Authors: D C Jewett, James H. Woods, Henry I Mosberg
    Abstract:

    The present study assessed the discriminative stimulus effects of the delta-opioid agonist [ d -Pen^2- d -Pen^5]enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injections of 100 µg [ d -Pen^2- d -Pen^5]enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of discriminative control was rapid (14–28 daily sessions). [ d -Ser^2, Leu^5, Thr^6]enkephalin (DSLET) and [ d -Ala^2]deltorphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (0.032–100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01–1 mg/kg, IM), and the Mu-Opioid Agonists, DAMGO (0.1–3.2 µg, ICV) and morphine (1–10 mg/kg, IM), did not produce discriminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Naltrindole (0.1 mg/kg, IM), an antagonist selective for deltaopioid receptors, produced approximately a 30-fold reduction in the potency of DPDPE. DPDPE's discriminative stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo.

  • Discriminative stimulus effects of a centrally administered, delta-opioid peptide (o-Pen2-o-PenS-enkephalin) in pigeons
    1996
    Co-Authors: I. Mosberg, James H. Woods
    Abstract:

    The present study assessed the discriminative stimulus effects of the delta-opioid agonist (D-Pen2-D - PenS)enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injec- tions of 100 gg (D-Pen2-D-PenS)enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of dis- criminative control was rapid (14-28 daily sessions). (D- Ser 2, Leu 5, Thr6)enkephalin (DSLET) and (D-Ala2)del - torphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (0.032-100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01-1 mg/kg, IM), and the Mu-Opioid Agonists, DAMGO (0.1-3.2 gg, ICV) and morphine (1-10 mg/kg, IM), did not produce dis- criminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Nattrin- dole (0.1 mg/kg, IM), an antagonist selective for delta- opioid receptors, produced approximately a 30-fold re- duction in the potency of DPDPE. DPDPE's discrimina- tive stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo.

  • Discriminative stimulus effects of a centrally administered, delta-opioid peptide (o-Pen2-o-PenS-enkephalin) in pigeons
    1996
    Co-Authors: I. Mosberg, James H. Woods
    Abstract:

    The present study assessed the discriminative stimulus effects of the delta-opioid agonist (D-Pen2-D - PenS)enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injec- tions of 100 gg (D-Pen2-D-PenS)enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of dis- criminative control was rapid (14-28 daily sessions). (D- Ser 2, Leu 5, Thr6)enkephalin (DSLET) and (D-Ala2)del - torphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (0.032-100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01-1 mg/kg, IM), and the Mu-Opioid Agonists, DAMGO (0.1-3.2 gg, ICV) and morphine (1-10 mg/kg, IM), did not produce dis- criminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Nattrin- dole (0.1 mg/kg, IM), an antagonist selective for delta- opioid receptors, produced approximately a 30-fold re- duction in the potency of DPDPE. DPDPE's discrimina- tive stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo.