James H. Woods - US grants

The Drug Abuse Basic Research Program in the Department of Pharmacology of the University of Michigan is composed of established investigators who have independent, but interrelated, interests in problems related to drug abuse. Studies in the monkey colony are concerned with the development of physical dependence to new analgesic drugs, to morphine antagonists and to compounds which have mixed agonist-antagonist properties. Self-administration studies in rhesus monkeys are used to evaluate the reinforcing properties of drug-taking behavior. Biochemical studies are concerned with the influence of drugs upon neuronal membrane binding.

The long term objectives of this research project are to identify and characterize beharioral, pharmacological, and environmental factors that affect drug-taking behavior, and to establish some general principles that relate to drug-taking behavior. In the upcoming grant period, the focus of the research wil be on the discriminative, reinforcing and direct actions of narcotis on operant behavior. Among the studies proposed are ones investigating the discriminative stimulus effects of the d-isomers of several narcotics, the ability of animals to discriminate between narcotic. That are though to act via different receptors, the effect of drug dependence on the reinforcing effects of drugs, the sterospecific nature of the reinforcing effect of narcotics, the ability of some narcotic drugs to attenuate punished responding, and the development of supersensitivity to narcotic antagonists. Additional projects will be concerned with the actions of narcotics and related drugs on systems involved with pain, consummatory behavior, and respiration. Several of the projects are involved with narcotic drugs that exert their actions through different narcotic receptor types. The projects utilize a broad set of different species: rhesus monkeys, pigeons, rats, mice and rabbits will be used in attempts to establish generality of results across situations and species.

This proposal is designed to evaluate the behavioral effects of antagonists of N-methyl-D-aspartate, and compare these effects to those of PCP and related compounds. Among the PCP-specific assays that will be used are PCP discrimination and catalepsy in the pigeon and ketamine discrimination in the monkey. Identification of behiaviors in the rat related to binding at the newly discovered signma receptor is the second goal of this proposal. These data may produce new leads for treatment of psychosis. Finally, procedures that may assist in measuring memory disturbances related to pharmacologically-induced Alzheimer's disease are proposed. The effects of excitatory amino acids and their antagonists will be evaluated in this procedure. These studies are predicated on recent reports of an inhibitory effect of PCP and ketamine on excitatory amino acid neurotransmission , and the finding of a novel binding site for psychotomimetic opiates. These findings have produced tremendous excitement about new drug development and the possibility of further understanding about the mechanism of action of PCP and related compounds. Because PCP is subject to abuse, produces signs similar to those of schizophrenia, is a prototype for a novel anesthetic, and has anticonvulsant activity, it is of considerable interest to evaluate its mechanism closely. Data that indicate that excitatory amino acids have neurotoxic effects, including the possibility of a relationship to Alzheimer's disease, increase interest in antagonists of excitatory amino acid actions. Most of the excitement about PCP has been generated by biochemical and electrophysiological work. It is essential that careful behavior studies be undertaken using the new drugs that have been recently synthesized or identified as being related to excitatory amino acid transmission. Behavioral data will permit a more rational integration of information coming from other in vivo and in vitro procedures.

There has been an explosive growth in information about glutamate-related excitatory amino acids and their antagonists in the last decade, and it would appear that the interest in these compounds will continue. They are fascinating at a basic science level (e.g., how do they function as neurotransmitters; are they functionally related to each other?) and at an applied level (might they be useful in treating stroke; are they involved in degenerative mental diseases; do they have specific effects on learning and memory; what is the mechanism by which they serve as reinforcers?). Despite the interest in function, the vast majority of studies of these drugs have involved electrophysiological, neuroanatomical, or neuropharmacological procedures. There are a very limited number of selective agonists or competitive antagonists available, and those that do exist often have limited access to the brain. Thus, little is known about their behavioral effects or their function in integrated systems. Although there are difficulties involved in studying many of these drugs at a behavioral level, we propose to continue our efforts in this direction. We will continue to evaluate the noncompetitive NMDA antagonists that act on the PCP receptor site and attempt to understand why some of these drugs, all of which should and most of which do have nearly identical effects, are slightly or markedly different in their behavioral profile. We will attempt to determine whether parenterally administered NMDA acts through central mechanisms or, as some of our data suggest, through peripheral mechanisms to affect behavior. We will evaluate the direct effects of glutamate agonists, given parenterally or centrally, on behavior in the pigeon to characterize these effects and the ability of selective antagonists to block these effects. We will continue to attempt to train NMDA and competitive NMDA antagonists as discriminative stimuli in pigeons and add experiments that attempt to train AMPA and kainate as discriminative stimuli as well. We will continue with efforts to understand the mechanism by which kainate and NMDA increase water intake in pigeons, We will continue to compare competitive NMDA antagonists and noncompetitive NMDA antagonists for their ability to produce anesthesia, act as reinforcers, and produce tolerance and cross-tolerance. Finally, we would like to begin studies that evaluate the effects of these agents on specific attributes of learning and recall in pigeons.

The broad objectives of this application are to evaluate oral opioids as reinforcers in rhesus monkeys so that this method of studying drug abuse might eventually be utilized in research in which drug use our the life- course of individual monkeys, in social setting, might be studied. Although there is an abundance of research on the reinforcing effects of orally delivered drugs from a number of drug classes, there has been very little published research on oral opioids as reinforcing stimuli. This is unfortunate because opioid abuse in humans is a problem of long standing, and because the opioid drug class includes such a wide variety of pharmacological tools for further understanding the nature of these drugs as reinforcers. For example, a large number of opioids with similar mechanisms but differing potencies are available for evaluation as oral reinforcers. From these it can be determined whether the rank order potency relationship that has been observed in a number of other preparations will be maintained under conditions in which the drugs are evaluated for the oral reinforcing effects. The effects of weekly administration of an irreversible opioid antagonist on drinking of a selected opioid drug will be observed to assure that the opioid effects are responsible for the consumption of the drug solutions. In an additional group of monkeys, the effects of food-deprivation on establishment and maintenance of opioids as reinforcers will be studied. The role of drug taste in the establishment, maintenance, and extinction of opioid drinking will be studied extensively in the proposed research. A preparation in which taste thresholds can be established is described. Data from studies of taste thresholds with different drugs will provide assistance in interpretation of information about the reinforcing effects of the opioid drugs with different pharmacological potency, but perhaps similar taste qualities. The use of inactive optical isomers of opioids, which should also have taste properties in common with the active isomers, will also help in identifying the role of taste in oral consumption of drugs. Another set of experiments, designed to aid in the interpretation of results of studies on opioids as reinforcing stimuli, involve drug discrimination studies. These will be used to determine the onset and duration of action of orally administered drugs, since onset of drug action may play an important role in determining whether all opioids come to serve as reinforcing stimuli when they are delivered orally.

The primary purpose of this proposal is three-fold: 1) to continue to evaluate the behavioral effects of drugs that act as agonists or antagonists at the NMDA subtype of the glutamate (excitatory neurotransmitter) receptor; 2) to begin to understand more of the behavioral pharmacology of nitric oxide primarily by using nitric oxide synthase inhibitors; and 3) to use newly available drugs that have parenteral activity to study the behavioral pharmacology of the AMPA subtype of the glutamate receptor. With respect to item 1), it has been found that the NMDA receptor contains sites for glycine as well as glutamate, and both of these excitatory amino acids ar necessary to activate this receptor. We have studied the interaction between agonists and antagonists at both these sites extensively in the mouse. The current proposal will extend these interaction studies to the pigeon and the monkey using primarily rates of food-maintained responding and discriminative stimulus effects as assays. With respect to item 2), it has been found that activation of the NMDA receptor results in production of nitric oxide from L-arginine, catalyzed by nitric oxide synthase. Similar effects of nitric oxide synthase inhibitors and PCP have been found in our studies of the discriminative stimulus effects of PCP. Part of the rationale for the proposed studies is to determine how much of the effects of PCP-like drugs and other NMDA antagonists and agonists are through NO formation. With respect to item 3), there has been very little work done on the in vivo effects of AMPA agonists and antagonists, because parenterally active drugs are only recently available. The behavioral effects of these drugs will be evaluated during this grant period. In addition to the effects of a number of EAA agonists and antagonists on rates of responding and their ability to serve as discriminative stimuli, a number of studies of the effects of these drugs on learning and memory in the pigeon are planned. Each of the three areas described above (glycine:glutamate; NO; AMPA) have well-characterized effects on long-term potentiation in the hippocampus, and less well-characterized effects on learning in animals. This is a fascinating and important area that will be explored in depth in this grant period.

stimulus /response; psychopharmacology; food; operant conditionings; electrostimulus; shock; buprenorphine; behavioral /social science research tag; Macaca mulatta; behavior test;

analog; opioid receptor; receptor binding; neuropharmacology; codeine; cell adhesion molecules; laboratory mouse;

nonhuman therapy evaluation; respiratory pharmacology; pulmonary respiration; drug addiction; naltrexone; morphine; drug abuse chemotherapy; chemoprevention; buprenorphine; drug tolerance; drug withdrawal; hypercapnia; respiratory airway volume; plethysmography; Macaca mulatta;

psychopharmacology; discrimination learning; drug abuse; opiate alkaloid; opioid receptor; fentanyl; heroin; naltrexone; morphine; drug vehicle; neuropharmacology; behavioral /social science research tag; Macaca mulatta; behavior test;

prostaglandin E

DESCRIPTION: (Applicant's Abstract) Pharmacotherapies useful in the treatment of cocaine abuse have proven very difficult to identify. The traditional receptor antagonist approach does not appear appropriate for cocaine for a number of reasons. This proposal is designed to evaluate five protein-based medications that may be effective in blocking the behavioral and toxic effects of cocaine. Three of these medications are antibodies that have been raised against cocaine in mice. A fourth medication is butyrylcholinesterase, the enzyme that breaks down cocaine in the blood. The fifth medication is a novel catalytic antibody, Mab 15A10, which may combine the properties of binding and metabolizing. Each of these medications is postulated to act to reduce the rate of cocaine entry into the brain, either by a process of sequestration, or by a process of rapid breakdown, or both. This decrease in rate of brain entry should decrease both the toxicity and the abuse liabililty of cocaine. The test procedures for toxicity involve evaluation of the ability of several doses of each of these medications to block cocaine-induced blood pressure increases in rats and mice. As a control, a drug with a similar structure and action as cocaine, but without the esteratic bridge where BChE and Mab 15A10 act, will be evaluated in parallel with cocaine. The duration of cocaine antagonism, a critical aspect of a medication, will be evaluated using the blood pressure assay in mice. The test procedure for treatment of the abuse of cocaine is intravenous self-administration studies in rats. Here too, dose-response curves with cocaine and WIN 35065 will be established, and attempts to shift these curves to the right will be made with administration of each of the five medications. Studies in which the ability of BChE and Mab 15A10 to produce increases in the cocaine metabolite, egconine methyl ester are planned to demonstrate that both of these medications increase the rate of cocaine metabolism.

DESCRIPTION (provided by applicant): The long-term objectives of this proposal include determining whether human butyrylcholine-esterase (BChE) might be of use in the treatment of cocaine-induced toxicity and abuse and to compare the effects of BChE with those of a more active mutant BChE. BChE will be purified from human blood by Dr. Lockridge at the University of Nebraska Medical Center. Dr. Lockridge will also purify a mutant of human BChE (A328W) as it is secreted by cultured cells. Then, at the University if Michigan, rhesus monkeys will be studied for their response to human BChE under three circumstances that involve cocaine administration. The ability of the BChEs 1) to modify the effects of cocaine on food-reinforced behavior; 2) to modify the reinforcing effects of cocaine; and 3) to alter the cardiovascular effects of cocaine will be studied in these animals. The dose-related effects of the BChEs will be studied extensively, as will the ability of repeated administration of effective doses of the BChEs to continue to modify the behavioral and cardiovascular effects of a range of doses of cocaine. In addition, particular attention will be paid to the duration of the effect of different doses of human BChE. The possibility that human BChE can eventually be used as a safe and effective treatment of cocaine abuse and toxicity is being explored through these studies.

DESCRIPTION (provided by applicant): A role for stress and CRH activation in acquisition, maintenance, and reinstatement of drug abuse is becoming more established. CRH antagonists are therefore of considerable interest as potential pharmacotherapies for drug abuse, both when it occurs alone, and when it is modified by stressful stimuli. Until recently, there were no significantly active CRH antagonists available for study. With the recent synthesis of small molecule antagonists and of novel, potent peptide antagonists, the means to probe these questions are much more available, and the research and therapeutic potential much more exciting. The purpose of this proposal is to characterize one new small molecule CRH1 receptor antagonist, antalarmin, one "ultra-new" small molecule CRH1 receptor antagonist, R 121919 and one new peptide CRH1/CRH2 receptor antagonist, astressin B. These characterizations will be done in rats using five measures of stress: i.v. administration of CRH, i.v. administration of the CRH R1 agonist EG12114, footshock, social defeat, and food deprivation. Initially, the effect of each stressor on ACTH and corticosterone levels will be determined. Then the ability of the antagonists to block the stress-induced increases in ACTH and corticosterone levels will be measured and the duration of this antagonism recorded. The antagonists will next be tested for their ability to modify rates and patterns of food, cocaine and remifentanil self-administration in unstressed rats. The effects of some of the stressors on rates and pattern of food and drug self-administration will be evaluated using a schedule of reinforcement that is resistant to the direct effects of the reinforcers, and the ability of each of the antagonists to modify stress-induced alterations in drug intake will be determined. Finally, the ability of the stressors to reinstate extinguished responding for food and drug will be determined and the effects of the antagonists on this effect of stress evaluated. These experiments are designed to characterize the CRH antagonists, and then to test their ability to modify drug self-administration, either as it is modified by stress, or in the absence of overt stress, and their ability to modify stress-induced reinstatement. This may provide information about the etiology of drug abuse, as well as data on the potential treatment of drug abuse in normal, or particularly, in stressed individuals.

DESCRIPTION (provided by applicant): Alcoholism is a major public health problem in the United States, resulting in the annual death of tens of thousands of Americans and costing billions of dollars. The development of animal models of alcoholism will play an important role in understanding the biological factors that contribute to the development of alcoholism and provide a means of testing novel medications for its treatment. A nonhuman primate model of alcoholism has been developed at the NIAAA's Laboratory of Clinical Studies in which animals are subjected to one of three different rearing manipulations that are designed to expose them to varying degrees of early life stress. When tested years later, significant group differences in oral ethanol self-administration behavior are observed. The first aim of the current application is to generate a detailed neuroendocrinological profile for eight monkeys in each of the three rearing groups (n=24) by measuring the dose-effect and time-course of the HPA axis response to the alpha 2 adrenergic antagonist yohimbine, the mixed serotonin agonist mCPP, the benzodiazepine receptor inverse agonist beta-carboline-3-carboxylic acid ethyl ester, and the putative CRHR1 receptor agonist EG1. The second aim is to quantify individual and group differences among the animals in their motivation to intravenously self-administer ethanol by examining the extent to which they persist on a progressive ratio schedule of intravenous ethanol reinforcement. The third aim is to determine whether there are individual and/or group differences in the effect that the pharmacological stressors administered in Experiment 1 have on progressive ratio performance for intravenous ethanol self-administration when given as pretreatments. These studies will contribute to a better understanding of the biological basis of alcoholism, which is a first step toward the development of effective pharmacotherapeutic interventions.

[unreadable] DESCRIPTION (provided by applicant): Cocaine esterase (CocE) is a product of the bacterium Rhodococcus sp. which grows in the rhizosphere of coca plants in South America. The bacterium uses cocaine as its sole source of carbon and nitrogen, synthesizing CocE to initiate metabolism of the cocaine CocE is the most efficient enzyme (7.2 X 108) for metabolizing cocaine yet identified. It can both prevent and reverse extreme cocaine toxicity in our rodent models, and it has the potential to be developed into the first useful antagonist of cocaine's toxic effects. This proposal contains studies to continue to evaluate this enzyme in mouse and rat models of cocaine toxicity, to compare its effects with other protein-based anti-cocaine enzymes, and to use a variety of in vitro techniques, including pegylation and insertion into red blood cells, to improve this or other enzymes by reducing their antigenicity, and heat liability. These procedures are designed to prolong the enzyme's duration of action with the hopeful outcome that some insight will be obtained into how to make this substance useful in the long-term treatment of cocaine abuse. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Enhancing cocaine metabolism by administration of cocaine esterases has been recognized as a promising treatment strategy for cocaine overdose and addiction. The esterase CocE is the most efficient native enzyme for metabolizing naturally occurring (-)-cocaine yet identified. Through catalysis of (-)-cocaine hydrolysis, CocE can both prevent and reverse extreme (-)- cocaine toxicity in rodent models and it has the potential to be developed into a chemically useful antagonist of the toxic and behavioral effects of (-)-cocaine. In order to optimize the efficacy of this potential anti-cocaine medication and minimize its possible side effects (particularly immunogenicity), we propose to improve the catalytic efficiency of CocE against (-)- cocaine. The higher the catalytic efficiency of the enzyme against (-)-cocaine, the lower the dose required to achieve therapeutic effectiveness and the decrease in dose can reduce the overall immunological response. Hence we will focus on the rational design, discovery, and preclinical testing of CocE mutants with an improved catalytic efficiency against (-)-cocaine. The rational design of high-activity mutants of CocE against (-)-cocaine requires a detailed understanding of the mechanism for CocE-catalyzed hydrolysis of cocaine. This mechanism can be understood by performing computational studies using the state-of-the-art computational techniques of molecular modeling, simulation, and calculation. The specific aims include: (1) Elucidation of the detailed mechanism and reaction coordinate and the corresponding free energy profiles for CocE-catalyzed hydrolysis of cocaine by performing quantum mechanical (QM) calculations, hybrid quantum mechanical/molecular mechanical (QM/MM) calculations, and molecular dynamics (MD) simulations, etc. (2) Design, discovery, and testing of CocE mutants with an improved catalytic efficiency against (-)-cocaine by using a recently developed novel computational design approach based on the transition state modeling and simulation to computationally evaluate a large number of hypothetical CocE mutants, followed by wet experimental tests including site-directed mutagenesis, protein expression and purification, and in vitro and in vivo activity tests. The long-term objective of this investigation will be to eventually develop an efficient anti-cocaine medication using a high-activity mutant of CocE. PUBLIC HEALTH RELEVANCE: Enhancing cocaine metabolism by administration of cocaine esterase (CocE) has been recognized as a promising treatment strategy for cocaine overdose and addiction. The high-activity mutants of CocE to be designed and discovered in this project will eventually lead to an efficient anti-cocaine medication.

DESCRIPTION (provided by applicant): Compulsive behaviors, including excessive eating, gambling, shopping, exercising, or drug-taking, can develop over time in individuals without other psychopathology. Although compulsive behavior is marked by excessive engagement in a particular behavior, animal models of compulsive behavior suggest that another defining feature is behavior that is disconnected from reinforcer delivery. Thus, people may gamble compulsively even though they do not win often, or shop excessively even when they may not use what they have purchased. Our hypothesis is that these types of reinforcer- disconnected behaviors result when both operant (instrumental, goal-tracking) and respondent (Pavlovian, classical, sign-tracking) conditioning processes converge on the same behavior. In addition, individuals must be sensitized to dopamine, and the compulsive behavior is more likely to occur in the presence of a D3/D2 agonist acting on the sensitized dopamine receptors. We will test this hypothesis in three behavioral models: 1) quinpirole-induced responding for stimuli associated with cocaine;2) quinpirole-induced responding for water in the presence of water;and 3) quinpirole as an occasion setter for either cocaine or water-reinforced behavior. The behavioral pharmacology of these models will be tested with various dopamine agonists and antagonists, and the roles of sensitization, goal-tracking, and sign-tracking will be studied. Understanding the environmental, behavioral, neurochemical, and pharmacological aspects of compulsive disorders will hopefully contribute to the development of treatments for these debilitating disorders. PUBLIC HEALTH RELEVANCE: The purpose of this proposal is to determine various environmental and neurochemical contributors to compulsive behavior (e.g., excessive gambling, shopping, eating, sexual behavior, and drug-taking). Our hypothesis, that compulsions result when the same classically conditioned and operantly conditioned behavior is established in the presence of sensitized dopamine receptors and stimulation of dopamine receptors, will be tested in three rat models in this research effort. Evaluation of the ability of selective dopamine receptors, as well as silencing the RNA for the D3 receptor, to modify the compulsive behavior should help point towards possible pharmacological treatment of these disorders, and understanding of the setting conditions will suggest behavioral therapy and prevention approaches.

? DESCRIPTION (provided by applicant): The recent reports that scopolamine has antidepressant effects in humans has raised the hope that this antimuscarinic drug represents an improvement over the serotonergic and noradrenergic reuptake blockers that have formed the basis for antidepressant medication for decades. Scopolamine's effects had a rapid onset of action, and were quite long lasting, giving them considerable advantage over previous medications. Of concern for the use of scopolamine in the treatment of depression is that scopolamine is used extensively in both human and animal studies to model cognitive deficits and dementia. There is, therefore, the likelihood that the antidepressant effects of scopolamine will coexist with the drug's well-known detrimental effects on attention, learning, and memory. The hypothesis on which the current proposal is based is that these two effects can be separated. They may, for example, be mediated by distinct receptor subtypes or by different efficacies at those receptors. Our plan is to evaluate selected antimuscarinic drugs in a series of coordinated assays designed to understand their profiles of activity. The assays will begin with in vivo evaluations to ascertain if a drug is a muscarinic antagonist centrally and peripherally. I so, its effects in antidepressant, and learning and memory assays will be described, and if a significantly smaller dose is necessary to produce antidepressant-like effects than to disrupt cognitive performance, its affinity and efficacy at the five muscarinic receptor subtypes will be measured. This will determine whether it is selectivity at one or more receptor subtype that confers antidepressant effects with reduced anti-cognitive effects. Chemical modeling will be applied to candidate compounds in attempts to improve their spectrum of activity so that there is an even greater pharmacological distinction between the desired and the off-target effects. Data obtained with our lead compound, L687,306 encourage our attempts to pursue this goal. According to the literature, L 687,306 is an M2 and M3 antagonist, has very slight efficacy at the M1 receptor, and is able to ameliorate the effects of scopolamine in cognitive tests. In our assays, it blocks the cardiovascular effects of arecoline, has discriminative stimulus effects in common with scopolamine, and is as active as scopolamine in the antidepressant assay. It is distinct from scopolamine in that it does not suppress ongoing behavior even at large doses, and it is able to competitively antagonize the suppressant effects of arecoline, which scopolamine cannot do. We anticipate that L 687,306 will have little effect on memory and attention until large doses are administered, since this drug has very little sedative effect and antagonizes scopolamine's anticognitive effects in similar assays. In vitro assays will indicate how the binding profile of L 687,306 differs from that of scopolamine, and on this basis, chemical modeling will be applied to improve on the presumed critical distinction. Through this process, we anticipate being able to specify the receptor mechanisms by which muscarinic antagonists ameliorate depression, how these are distinct from those that lead to impaired cognition, and to designate chemical entities that are likely to have an improved profile of antidepressant activity.

Methocinnamox (MCAM) is a long-acting µ-opioid receptor antagonist that may have distinct advantages in the treatment of both opioid overdose and opioid abuse disorder. We propose to evaluate MCAM using in vitro and in vivo measures, comparing the actions of MCAM with those of the opioid antagonists naltrexone and naloxone, that are currently used to treat abuse and overdose, respectively. We hypothesize that differences in pharmacological properties, including binding kinetics and non-surmountablility by opioids of abuse, will distinguish MCAM from those of the other opioid receptor antagonists. In vitro, we will compare MCAM to naloxone for kinetics of association/dissociation, surmountability by opioid agonists (fentanyl, morphine), the duration of antagonism (is MCAM irreversible?), and determine the pharmacological characteristics of MCAM at multiple cellular signaling pathways. In vivo measures will be taken in rats to ascertain the duration of action and insurmountability of MCAM in several relevant preparations. Reversal of ? opioid receptor agonist- (morphine and fentanyl) induced respiratory depression will be evaluated using whole body plethysmography. The relative duration of overdose protection afforded by MCAM versus naloxone will be measured in this preparation as well. Models of protection against opioid abuse will utilize measures of the reinforcing effects of the ? opioid receptor agonist remifentanil. The relative insurmountability and duration of action of MCAM versus naltrexone (currently used to treat abuse) in blocking the reinforcing effects of remifentanil will be established in this preparation. The smallest dose of MCAM that is effective when given daily in preventing the reinforcing effects of remifentanil will provide information on the rate of delivery that would be appropriate in a sustained-release formulation of MCAM. Comparisons will also be made of the relative ability of MCAM versus naloxone to elicit withdrawal in opioid- dependent rats. Lastly, because current µ opioid analgesic drugs will not be effective if a long-acting antagonist (e.g., MCAM) is used to treat abuse and/or overdose, we will assess the feasibility of peripherally-restricted administration of kappa opioid receptor agonists for use as analgesic agents in the presence of MCAM. Activation of peripheral kappa opioid receptors that are expressed on peripheral pain-sensing neurons can produce a level of analgesia equivalent to that produced by a local anesthetic and therefore may be a good approach for the treatment of pain in individuals with long-term blockade of µ opioid receptor function. Together, this work will provide needed information about whether MCAM offers substantial advantage over naloxone and naltrexone in blocking or preventing the actions of opioid drugs of abuse.