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PubMed1989

The assessment and treatment of pain in the emergency room.

A broad spectrum of painful conditions presents to the modern emergency center (EC). The three most common categories are acute, self-limited disorders; chronic medical or surgical syndromes with acute exacerbation; and psychic pain syndromes in which the etiology cannot be easily ascertained. Many factors may differentiate pain from suffering, and physicians should educate patients not only about the nature of their condition and its prognosis, but also about anticipated discomfort. Clinical concerns in the EC include physicians' tendency to undertreat or even ignore pain, the need for appropriate but flexible dosage schedules, and physicians' concern about masking important signs and symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the safest and most effective group of oral analgesics. Important factors for drug selection include efficacy, dosage, lack of side effects, and cost. Two special groups of patients, those with psychic pain syndromes and those with drug-seeking behavior, can create problems for the physician. Patients with chronic pain syndromes need special follow-up but do not benefit from additional analgesic drug therapy. Patients who seek and abuse drugs can be difficult to identify, may have true underlying medical pathology, and should not be given narcotic prescriptions.

Adult↗
PubMed2026

Refinement of Nucleus Accumbens Neuronal Dynamics during Cocaine Self-Administration Training.

Drug addiction is an acquired motivational-behavioral state that begins with drug taking, which is composed of a series of phases, including initial acquisition, stabilization, habituation, and maintenance. In rodent models of cocaine self-administration, the forebrain region nucleus accumbens (NAc) has been critically implicated in the acquisition-maintenance process of drug-taking and drug-seeking behaviors. However, it remains unknown how NAc neurons shift their activity patterns in response to these phasic transitions during cocaine taking. To examine this, we used GCaMP6m-based in vivo Ca2+ imaging in male mice to monitor activities of principal medium spiny neurons (MSNs) in the NAc across 11 d of cocaine self-administration. Behaviorally, mice exhibited progressive stabilization of operant responding and locomotion across 11 d of cocaine self-administration. During the early training days, we detected a portion of NAc neurons-a potential neuronal ensemble-that exhibited increased activities temporally contingent to the lever-press for cocaine. The number of NAc neurons exhibiting contingent activity increased progressively over the first three training days and then decreased gradually during the later training days, exhibiting expansion-refinement dynamics that may correspond to the acquisition and subsequent stabilization/maintenance of cocaine self-administration. Using a neuron-tracking technique, we found that the lever-press-contingent NAc ensemble exhibited substantial compositional dynamics, with neurons dropping into and out across training days. These activity features of lever-press-contingent neurons may represent key circuit dynamics of the NAc that transition the acquisition toward the maintenance of cocaine-taking behavior.

Animals↗
PubMed1975

[Dependence on and preference for morphine (II). Comparison among morphine, phenobarbital and diazepam].

Results of a previous experiment indicated that naive rats given a choice between morphine-admixed food (0.5 similar to 1mg/g of food) and quinine-admixed food (0.5 similar to 1 mg/g of food) for 3 weeks gradually and spontaneously preferred the morphine-admixed food, and this choice behavior revealed one of the psychological aspects of morphine dependent rats. In the present work, the ability of preference formation was detected for morphine, phenobarbital and diazepam by a defferent chioce test using drug dependent rats. Rats were pretreated with morpnine, phenobarbital, and/or diazepam by drug admixed food ingestion method for 12 similar to 15 weeks, and the choice test was practiced for one week at 3 intervals (4 similar to 5 trials). Control groups of rats were given the same choice testas the naive rats. Results indicated that (a) of all the drugs employed, morphine showed the most rapid and intensive preference formation (b) Phenobarbital and diazepam had almost the same degree of preference formation. (c) Phenobarbital showed no dose-dependent intensity of preference formation in the 50-90 mg/kg/day dose range, however, a more rapid development of preference was observed dose-dependently among the 80-120 mg/kg/day dose range of diazepam. Thus these studies utilizing a choice test provide a clear demonstration of drug-seeking behavior in rats. In addition, the present method is useful for drug screening tests involving weak psychological dependence liability, and moreover, the data could be analyzed statistically.

Animals↗
PubMed1992

Regulation of opioid gene expression: a model to understand neural plasticity.

The recent finding that neurotransmitters and drugs that affect neurotransmission have important influences on gene expression suggests that drug-induced alterations in gene expression may underlie many long-term effects of addictive drugs, for example, dependence and drug-seeking behaviors. These long-term adaptive responses to opiate drugs have been particularly difficult to understand at a mechanistic level. Data presented here indicate that the gene encoding the opioid precursor proenkephalin is highly regulated by neural activity, second-messenger pathways, and PKA. These observations raise the possibility that drugs of abuse (e.g., opiates acting through opiate receptors) may act at the genetic level to modulate the expression of endogenous opiates and that these effects may underlie one component of the brain's long-term adaptive response to exogenous opiates. The transgenic animals described above can be used to investigate opiate drug-induced changes in proenkephalin gene expression, allowing rapid analysis of changes in proenkephalin gene expression in highly restricted populations of neurons in a fashion previously impossible. In addition, by analyzing the effects of specific enhancer mutations on tissue-specific and transsynaptic regulation of proenkephalin expression, transgenic models will permit mechanistic investigations within the intact nervous system that cannot otherwise be undertaken. Investigation of mechanisms underlying this process requires the analysis of intracellular signaling pathways, responsive DNA regulatory elements, and the transcription factors transducing synaptic signals into gene regulation. In the studies described herein, we demonstrate that AP-1 complexes consisting of different Jun proteins differentially regulate proenkephalin transcription at the CRE-2 element. c-Jun constitutively activates proenkephalin transcription, whereas JunD activates in a fashion completely dependent on the activation of second-messenger pathways and the cAMP-dependent PKA. JunB alone has no effect on proenkephalin gene expression, yet this molecule effectively blocks activation mediated by JunD and, hence, may act as a repressor. These data are consistent with a model (figure 4) in which preexisting JunD mediates the rapid cAMP-dependent activation of the proenkephalin enhancer, whereas IEGs such as JunB or c-Fos mediate the protein synthesis-dependent inactivation. Because c-Jun activates proenkephalin transcription constitutively, induction of c-Jun may lead to a further and prolonged activation of proenkephalin gene expression. Hence, the ratio of c-Jun to JunB induction may determine whether proenkephalin is repressed or further activated.

Animals↗
PubMed1992

Emergency management of acute pain. New options and strategies.

Emergency physicians often encounter patients in pain and may also have to cope with other problems (eg, alcohol intoxication, a patient's stubborn will to drive after the emergency department visit, narcotic "allergy"). Novel approaches can be used to treat these patients. Dr Heller discusses such approaches, including measures for treating patients with drug-seeking behavior (eg, use of nonnarcotic parenteral agents), and describes treatment options for patients with such specific conditions as hypotension, chest pain, and renal colic.

Acute Disease↗
PubMed1992

Buprenorphine: an alternative to methadone for heroin dependence treatment.

Eighty-five heroin addicts who were unwilling to receive methadone maintenance or enter therapeutic communities were assessed, single-blind, for the lowest sublingual dose of buprenorphine that blocked heroin craving (8.0 mg max). All doses were administered daily under observation. After maintenance for 4 to 12 weeks, abstinent subjects (confirmed by urine drug screens) entered a double-blind discontinuation trial and were randomly assigned to receive dose reductions (10% twice weekly for 5 weeks to zero dose, then placebo for 2 weeks) or a stable dose for 7 weeks. Subjects were terminated from discontinuation if heroin was used or they had increased craving/symptoms. Subjects completed the trial if they did not use heroin and had no increase in craving/symptoms. A wide dose range (1.5-8.0 mg/day) was effective in reducing heroin craving and use. Of 73 subjects who received buprenorphine for 4 to 52 weeks, 40 had no prior treatment, despite high levels (mean $/day heroin = 70.5 +/- 94.7) and many years (mean years = 10.7 +/- 8.6) of dependence. Subjects who received dose reductions developed abstinence symptoms, low energy most commonly, associated with drug-seeking behavior. Discontinuation trial outcome (n = 51) shows a highly significant difference between 29 subjects who received dose reductions (28 terminated, 1 completed) and 22 subjects who received no dose reductions (3 terminated; 19 completed) (chi-square = 36.08; p less than .00001). The findings suggest that buprenorphine could be an important medication for reducing demand for heroin by many heroin addicts who remain outside the present health-care system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Butorphanol tartrate (stadol): a review.

Butorphanol tartrate (Stadol; Anaquest, Madison, WI/Bristol-Meyers Squibb, Evansville, IN) is an analgesic possessing mixed agonist-antagonist activity at opiate receptors. Receptor specificity has been used to limit respiratory depression, gastrointestinal side effects, and reduce the risk of dependency. Theoretically it offers an advantage over traditional opiates such as morphine and meperidine in the treatment of moderate pain. Butorphanol has been used as a preoperative sedative and analgesic, as a supplement to balanced anesthesia, and for suppression of postanesthesia shaking. Other recognized uses include obstetric analgesia during labor and relief of moderate postpartum pain. In addition, butorphanol has been used effectively for conscious sedation. Its lack of euphoric effects may be useful in emergency medicine for clinical populations prone to drug-seeking behavior. Butorphanol has been used more recently for epidural analgesia or for intravenous patient-controlled analgesia when allergies to opiates exist. Since butorphanol is not a controlled substance, its use can reduce administrative liability for abuse and can lower the number of distribution records associated with Schedule II narcotics.

Butorphanol↗
PubMed1990

The behavioral pharmacology of alcohol and other drugs. Emerging issues.

Alcohol and other drugs are compared with respect to their abuse liability and dependence potential. Drug-reinforced behavior is defined, and factors related to the establishment of this behavior that have received increasing experimental attention in recent years are reviewed. Acquisition techniques, schedule of access, route of self-administration, and organism factors, such as species, gender, and genetic background, are discussed. Other areas of emerging interest are the effect of feeding regimens, alternative reinforcers, and social conditions on drug-reinforced behavior. Also, biochemical factors such as neurochemical alterations, hormonal changes, and alcohol and other drug combinations, are considered. Finally, dependence potential is considered in terms of observational changes and performance alterations that seem to be sensitive indicators of the protracted aspects of drug withdrawal. The relationship between drug-seeking behavior and withdrawal is examined.

Alcohol Drinking↗
PubMed1979

Psychotropic drugs: a biopsychosocial approach.

A biopsychosocial theory and approach to drug-seeking behavior suggests new questions for the family physician to ask his patient when psychotropic drugs are being considered. The theory and rational guidelines for prescribing allow the physician to make more appropriate decisions when faced with difficult situations. Pharmacotherapy can then be directed toward alleviating anxiety that inhibits the patient's existing coping skills or toward activating the depressed/apathetic patient to use his existing skills. With this approach, social, psychologic and biologic coping devices can be simultaneously mobilized.

Drug Prescriptions↗
PubMed1990

Cholecystokinin and neurotensin mRNAs are differentially expressed in subnuclei of the ventral tegmental area.

Immunohistochemical studies of ventral tegmental area (VTA) neurons indicate that individual cells can contain dopamine as well as the neuropeptide neurotransmitters cholecystokinin (CCK) and neurotensin (NT). We have defined the distribution of the cells expressing the mRNAs encoding these two dopamine cotransmitter peptides in each of the subnuclei of the ventral tegmental area, and quantitated the extent of expression of each gene by using in situ hybridization methods. These studies reveal significant differences in the patterns of expression of each of these two genes within various subdivisions of the VTA. The rostral linear nucleus contained numerous CCK positive cells, some of which appeared to express preproCCK-mRNA at a very high level, but this nucleus contained relatively few NT-expressing cells. The parabrachialis pigmentosus contained numerous NT and CCK positive cells. The paranigralis and interfascicularis nuclei displayed positive CCK cells but with expression at only modest levels. NT cells were very few in these nuclei. The caudal linear nuclei contained the highest number of NT-expressing neurons and these cells expressed very high levels of NT mRNA. The selective distribution of these peptide genes within the VTA subnuclei may have specific consequences. Studies of the connectivity of neurons in the VTA show that the different subnuclei of this region project to several functionally and architectonically different regions of the cerebral cortex and subcortically to nuclei related to the limbic system. Results from our study show very prominent expression of CCK mRNAs in those subnuclei that project heavily to the prefrontal, other cortical areas, and the amygdaloid complex. The NT gene is expressed prominently in those subnuclei of VTA that project heavily to the entorhinal cortex and amygdaloid complex. These results provide support for a differential role for the NT-expressing neurons than that of CCK-expressing neurons of VTA in "reward" mechanisms and in drug-seeking and motivational behavior. These observations could be applied to create working hypotheses and experimental paradigms to test the differential functional activity of the subdivisions of VTA and their potential roles in the pathogenesis and treatment of drug-seeking behavior and other neuropsychiatric disorders.

Animals↗
PubMed1988

Predicting treatment outcome of chronic back pain patients in a multidisciplinary pain clinic: methodological issues and treatment implications.

Treatment outcome of 72 chronic back pain patients was assessed with 4 standardized measures: the McGill Pain Questionnaire, the Audiovisual Taxonomy of Pain Behavior, the Beck Depression Inventory, and the Profile of Mood States. Patients were also rated by their primary nurse on pain behavior, activity, drug-seeking, and sleep. Variables used to predict scores on outcome measures included patients' demographics and MMPI scores. Multiple regression analyses indicated that patients receiving worker's compensation engaged in more pain behavior and rated their pain as more severe, both upon admission and discharge from the pain program. High scores on the MMPI Hy scale were correlated with high self-ratings of pain and several MMPI scales correlated with negative mood. Even though demographic variables predicted admission and discharge scores on a number of treatment outcome measures, there was no relation between demographics and patients' improvement on treatment outcome measures. Patients with high scores on MMPI Hy and D scales displayed greatest admission to discharge improvement on self-rated pain and mood. Results were integrated with findings from previous studies. It was suggested that by distinguishing between overall scores on treatment outcome measures and improvement on these measures, professionals will be in a better position to devise individualized treatment plans for pain patients.

Adult↗
PubMed2025

Distinct Behavioral Profiles and Neuronal Correlates of Heroin Vulnerability Versus Resiliency in a Multi-Symptomatic Model of Heroin Use Disorder in Rats.

OBJECTIVE: The behavioral and diagnostic heterogeneity within the opioid use disorder (OUD) diagnosis is not readily captured in current animal models, limiting the translational relevance of the mechanistic research that is conducted in experimental animals. The authors hypothesized that a nonlinear clustering of OUD-like behavioral traits would capture population heterogeneity and yield subpopulations of OUD vulnerable rats with distinct behavioral and neurocircuit profiles. METHODS: Over 900 male and female heterogeneous stock rats, a line capturing genetic and behavioral heterogeneity present in humans, were assessed for several measures of heroin use and rewarded and non-rewarded seeking behaviors. A nonlinear stochastic block model clustering analysis was used to assign rats to OUD vulnerable, intermediate, and resilient clusters. Additional behavioral tests and circuit analyses using c-fos protein activation were conducted on the vulnerable and resilient subpopulations. RESULTS: OUD vulnerable rats exhibited greater heroin taking and seeking behaviors relative to those in the intermediate and resilient clusters. Akin to human OUD diagnosis, further vulnerable rat subclustering revealed subpopulations with different combinations of behavioral traits, including sex differences. Lastly, heroin cue-induced neuronal patterns of circuit activation differed between resilient and vulnerable phenotypes. Behavioral sex differences were recapitulated in patterns of circuitry activation, including preferential engagement of extended amygdala stress circuitry in males and cortico-striatal drug cue-seeking circuitry in females. CONCLUSION: Using a nonlinear clustering approach in rats, the analysis captured behavioral diagnostic heterogeneity reflective of human OUD diagnosis. OUD vulnerability and resiliency were associated with distinct neuronal activation patterns, posing this approach as a translational tool in assessing neurobiological mechanisms underpinning OUD.

Animals↗
PubMedDate not supplied

Treatment issues for opioid-dependent women during the perinatal period.

Opioid dependence has been studied with regard to its effects on the woman, the fetus, and the child for the past three decades, and it continues to be a serious problem that must be recognized and addressed by the health care delivery system in order to provide optimal medical care. The use of pharmacotherapy, such as methadone maintenance treatment (MMT), is only one of a variety of treatment modalities to provide optimal services for opioid-dependent women. The complete schema for treating opioid dependence in the perinatal period is complex and intense, but MMT serves multiple purposes. Primarily, it removes the addicted woman from the drug-seeking environment, eliminates the necessary illicit behavior, and prevents the peaks and valleys in the maternal heroin level that may occur throughout the day. In addition, maternal nutrition is usually improved and MMT patients become amenable to prenatal care and psychosocial rehabilitation. It is evident from the findings of numerous studies that when the physical, psychological, and socioeconomic issues of pregnant opioid-dependent women and their children are coupled with MMT, the potential physical and behavioral effects of psychoactive drugs on the mother, the fetus, the newborn, and the child may be markedly reduced.

Female↗
PubMed1991

Problematic behavior of drug-dependent patients in the general hospital. A clinical and administrative approach to management.

Drug-dependent patients in general hospitals behave in ways that are difficult for medical and surgical staff to manage. Common problems include drug-seeking, states of intoxication and withdrawal, poor compliance, and behavior that is disruptive or dangerous to others. The authors describe an approach to these problematic behaviors based upon early recognition, a clinical perspective, and administrative action. Institutional initiatives are needed to overcome the practical and conceptual obstacles to effective management of these patients.

Adult↗
PubMed1991

Hippocampal mu-receptors mediate opioid reinforcement in the CA3 region.

Dependence on reinforcing chemicals is manifested when drug-seeking and drug-taking behaviors come to dominate the response repertoire. Clinical observations suggest that the craving and compulsive drug-seeking that characterize drug dependence are aroused by memories of the reinforcing drug experience. If so, a brain structure intimately associated with memory--the hippocampus--would be a plausible substrate for drug reinforcement effects. We report here that drug-naive rats rapidly learn to self-administer the opioid peptide dynorphin A in the CA3 region of hippocampus, and that this behavior is blocked by co-administration of the non-selective opiate antagonist naloxone. Subsequent studies demonstrated that coadministration of mu-, but not kappa- or delta-opioid antagonists also blocked self-administration behavior. We conclude that mu-receptors in the CA3 region of hippocampus may be important target sites for opioid dependence.

Animals↗
PubMedDate not supplied

Genetically determined differences in the effects of morphine on mice.

We have compared a variety of well known behavioral actions of morphine across four strains of laboratroy mice. Thes measures included locomotor activation, analgesia, tolerance, dependence and drug-seeking. We found that analgesia and drug-seeking did not vary greatly among strains, although some statistically significant differences were found. The interstrain rank ordering for locomotor activity, tolerance and dependence was different for each of these measures. This suggests that each of these effects of morphine may depend upon separate mechanisms, perhaps with each under independent genetic control. Other experiments were carried out to determine whether or not there were differences in the in vivo brain uptake of an opiate or the in vitro binding of naloxone to 'stereospecific receptors'. No significant interstrain differences could be found.

Analgesia↗
PubMed1992

Drugs of abuse: behavioural principles, methods and terms.

Current understanding of drug abuse has been greatly influenced by the emphasis on drug-seeking behaviour as the common element. The three main attributes of drugs that maintain, direct and regulate drug-seeking behaviour are their positively reinforcing and discriminative and aversive stimulus properties. Each process may be analysed in terms of underlying behavioural and neural mechanisms that are mutually complementary and interactive. Environmental stimuli conditioned to the effects of the drugs also play a key role in eliciting and maintaining drug-seeking behaviour. Both the behavioural and the neural mechanisms are subject to modulating variables such as social, environmental and genetic factors, including the previous behavioural and pharmacological history of the individual. Thus, the behavioural approach to addiction does not preclude important roles for other factors, but rather seeks to integrate them into a comprehensive theoretical framework strongly linked to empirical data.

Animals↗