Pain and Addiction PubMed Abstracts

Prevalence And Correlates Of Alcohol Use Disorders In The Singapore Mental Health Survey.

Addiction. 2012 Feb 1;

Authors: Mythily S, Abdin E, Vaingankar J, Phua AM, Tee J, Chong SA

Abstract
Aims:  To establish the prevalence, correlates, comorbidity, and treatment gap of alcohol use disorders in the Singapore resident population. Design:  The Singapore Mental Health Study is a cross-sectional epidemiological survey. Setting:  A nationally representative survey of the resident (citizens and permanent residents) population in Singapore. Participants:  6616 Singaporean adults aged 18 years and older. Measurements:  The diagnoses were established using the World Mental Health Composite International Diagnostic Interview (WMH-CIDI) diagnostic modules for lifetime and 12-month prevalence of select mental illnesses including alcohol use disorders. Results:  The lifetime prevalence of alcohol abuse and alcohol dependence was 3.1% and 0.5%, while the 12-month prevalence of alcohol abuse and alcohol dependence was 0.5% and 0.3%, respectively. The lifetime and 12-month prevalence of alcohol use disorders was 3.6% and 0.8%, respectively. Those with alcohol use disorder had significantly higher odds of having major depressive disorder (OR 3.1) and nicotine dependence (OR 4.5). Compared to the rest of the population, those with an alcohol use disorder had significantly higher odds of having gastric ulcers (OR 3.0), respiratory conditions OR (2.1) and chronic pain (OR 2.1). Only 1 in 5 of those with alcohol use disorder had ever sought treatment. Conclusions:  The prevalence of alcohol use disorders is relatively low in the Singapore adult population. Comorbidity with mental and physical disorders is significant emphasizing the need to screen persons with alcohol use disorders for these comorbidities.

PMID: 22296228 [PubMed - as supplied by publisher]

Basic pharmacology of NMDA receptors.

Curr Pharm Des. 2012 Jan 18;

Authors: Gonda X

Abstract
NMDA receptors are ionotropic receptors mediating glutamatergic neurotransmission and play a role in several basic functions in the central nervous system, from regulating neurodevelopment and synaptic plasticity, learning and memory formation, cognitive processes, rhythm generation necessary for locomotor activity and breathing, and excitotoxicity. Due to their complex involvement in the above processes, NMDA receptors have been established to play a role in the etiopathology of several neuropsychiatric disorders such as ischemia and traumatic brain injury, neurodegenerative disorders, pain syndromes, addiction, affective disorders and such neurodevelopmental disorders as autism or schizophrenia. NMDA receptors contain multiple types of subunits with distinct functional and pharmacological properties making the picture more complex. These receptors also offer multiple binding sites to be targeted with pharmacons, however, early broad-spectrum NMDA receptor antagonists had limited clinical use due to their intolerable adverse effect profile. The discovery of several types of subunit selective NMDA receptor antagonists may offer valuable therapeutic possibilities for several disorders, with improved clinical efficacy and decreased side effects. However, in spite of our increasing knowledge concerning the involvement of NMDA receptors in pathological processes, molecules with a selective action, tolerable side effect profile and good clinical efficacy are still only in clinical development in the majority of cases. Nevertheless, NMDA receptors offer a novel opportunity in the treatment of various neuropsychiatric conditions.

PMID: 22280436 [PubMed - as supplied by publisher]

[Chronic peripheral arterial disease induced by cocaine].

Medicina (B Aires). 2012;72(1):37-9

Authors: Pankl S, Pellegrini D, Bruetman JE

Abstract
Cocaine induced acute peripheral thrombosis, though a rare complication, has been described in the literature. Although there are reports describing the chronic effects of cocaine on the peripheral arterial system, there are no published cases of this complication when other risk factors are lacking. We report on a 22 year old female patient, with intranasal consumption of 3 grams of cocaine per week for a year, who consulted for intermittent claudication at 200 meters, associated to left lower limb pain and paresthesiae for the last two months. Arterial Doppler ultrasonography showed a stenosis greater than 70% in the superficial left femoral artery. Other probable etiologies were excluded. Treatment was initiated with acetylsalicylic acid, cilostazol and graded physical exercise, associated to support therapy in order to maintain cocaine consumption avoidance, with good response. This case emphasizes the relevance of patients information, as most people ignore the cardiovascular complication of this addiction. It is also essential to inquire about cocaine consumption in young patients with peripheral arteriopathy and no apparent risk factors.

PMID: 22257455 [PubMed - in process]

Drug-dependent inpatients reporting continuous absence of spontaneous drug craving for the main substance throughout detoxification treatment.

Drug Alcohol Rev. 2011 Jul;30(4):403-10

Authors: De Los Cobos JP, Siñol N, Trujols J, Bañuls E, Batlle F, Tejero A

Abstract
INTRODUCTION AND AIMS: Drug craving is considered to be an essential component of substance dependence. We aimed to characterise drug-dependent inpatients reporting continuous absence of subjective spontaneous drug craving.
DESIGN AND METHODS: This is a 3 year chart-review study designed to compare drug-dependent inpatients who did not report craving everyday (non-cravers) and their counterparts who did (cravers). All participants were recruited consecutively and completed a 14 day detoxification treatment. Craving was defined as a desire to use the main detoxification substance. This substance was chosen by patients, who completed a craving visual analogue scale, the Beck Depression Inventory and the State-Trait Anxiety Inventory daily. The Temperament and Character Inventory and the Addiction Severity Index were also used.
RESULTS: Of the 195 patients who completed the detoxification treatment, 45 (23.1%) were non-cravers and 32 (16.4%) were cravers. The main detoxification substances were alcohol, benzodiazepines, cannabis, cocaine, heroin and methadone. Non-cravers named methadone as the main detoxification substance more frequently than cravers, and benzoylecgonine was less frequently present in their urine at treatment entry. A decreased score on the Temperament and Character Inventory dimension of harm avoidance (i.e. trait anxiety) was the only independent predictor of absence of craving (odds ratio = 1.16, 95% confidence interval = 1.03-1.31). During admission, non-cravers had lower Beck Depression Inventory and State-Trait Anxiety Inventory scores than cravers. These differences were not accounted for by pharmacological treatment.
DISCUSSION AND CONCLUSIONS: Drug -dependent inpatients who report absence of craving are characterised by relatively low levels of depression and anxiety throughout detoxification treatment, and relatively low levels of trait anxiety.

PMID: 21355930 [PubMed - indexed for MEDLINE]

Catechol-O-methyltransferase polymorphisms do not play a significant role in pain perception in male Chinese Han population.

Physiol Genomics. 2012 Jan 17;

Authors: Xiang X, Jiang Y, Ni Y, Fan M, Shen F, Wang X, Han J, Cui C

Abstract
Polymorphisms in the human catechol-O-methyltransferase (COMT) gene have been widely studied for their role in pain and analgesia. In this study, sensitivity to potassium iontophoresis, visual analogue scale (VAS) measurements for fixed two-fold pain threshold stimulation and pain threshold changes induced by transcutaneous electrical acupoint stimulation (TEAS) were assessed in a population of healthy Chinese males. These results were correlated with the alleles of six single nucleotide polymorphisms (SNP) or diplotypes of common haplotypes designated as low pain sensitive (LPS), average pain sensitive (APS), and high pain sensitive (HPS) in the COMT gene of these subjects. Our results reveal that the alleles of each SNP are not significantly correlated with pain perception except for the rs4633 allele in the 2 Hz TEAS session (p<0.05). In addiction, the six diplotypes of COMT haplotypes, which cover 92.5% of the Chinese population, are also not correlated with pain perception. Moreover, there were no significant differences in pain threshold changes induced by 2 Hz and 100Hz TEAS among the diplotypes of each SNP or the various haplotypes. These results suggest that COMT activity do not play a significant role in pain perception and TEAS-induced analgesia in the Chinese Han male population.

PMID: 22253202 [PubMed - as supplied by publisher]

Pain During Transcranial Magnetic Stimulation in Youth.

Innov Clin Neurosci. 2011 Dec;8(12):18-23

Authors: Coarkin PE, Wall CA, King JD, Andrew Kozel F, Daskalakis ZJ

Abstract
Pain or discomfort at the site of stimulation is a common side effect of transcranial magnetic stimulation. Relevant physiology and predisposing factors have not been adequately described. Literature regarding work with minors is even more limited. The authors present two cases from a child and adolescent neurophysiology transcranial magnetic stimulation protocol and one case from a therapeutic study of repetitive transcranial magnetic stimulation in adolescents with treatment-resistant major depressive disorder. Relevant literature is reviewed. Potential subjects, parents, and study teams should be well aware of this potential side effect in child and adolescent populations. Subjects with anxiety disorders may be prone to pain during these procedures. Further work could assist in identifying predisposed individuals, refining the informed consent process, and implementing procedures to minimize discomfort.

PMID: 22247814 [PubMed - as supplied by publisher]

[Trazodone in the treatment of addiction].

Pol Merkur Lekarski. 2011 Dec;31(186):384-7

Authors: Kryszkowski W, Bobińska K, Talarowska M, Orzechowska A, Florkowski A, Gałecki P

Abstract
The problem of addiction to psychoactive substances (SPA) is an important aspect of modem psychiatric treatment. This is due to the increasing number of addicts, and reducing their increasing age. It is estimated that in the United States in 2006, people aged over 12 years of meeting criteria for dependence on SPA was 20-25 million. Other statistics report that in the same age group over the last year contact with these substances were 8-10 percent of the U.S. population. Therefore, it becomes an important issue the appropriate therapeutic treatment of addicts. The result of the search of drugs that help people to alcoholism treatment program, were studies involving trazodone. Counted among the SARI (serotonin reuptake inhibitor and antagonist), shows antagonism to serotonergic receptors (5-HT2 receptors), while an inhibitor of serotonin reuptake. Its performance was analyzed in individuals dependent on alcohol, benzodiazepines and opiates, as well as mixed addictions. Also raised the problem of influence of trazodone on the experience of pain, which maybe helpful in relieving withdrawal symptoms. The data show a positive effect of trazodone in individuals addicted to the SPA, although the mechanism by which trazodone works in the body is very complex and not yet fully understood. Its advantage is the relatively small panel of side effects. Although many of the analyzed studies were not placebo-controlled, the results are so promising that you can recommend on the basis of trazodone therapy in individuals addicted to the SPA.

PMID: 22239013 [PubMed - in process]

Nonmedical prescription opioid use and mental health and pain comorbidities: a narrative review.

Can J Psychiatry. 2011 Aug;56(8):495-502

Authors: Amari E, Rehm J, Goldner E, Fischer B

Abstract
OBJECTIVE: In North America, the prevalence of nonmedical prescription opioid use (NMPOU), and morbidity and mortality related to prescription opioid analgesics (POAs) has risen sharply. Epidemiologic studies have suggested a high prevalence of mental health and pain comorbidities in NMPOU samples. Given the potential importance for interventions, a narrative review was conducted on studies reporting data on the co-occurrence of NMPOU with mental health problems and pain symptoms in general, treatment, or special populations.
METHOD: A search of MEDLINE, PubMed, PsycINFO, and Web of Science using defined search terms yielded 74 studies on NMPOU and mental health and (or) pain. Thirty-nine studies published between 1997 and 2009 were included in the review-based on the data they provided on NMPOU and mental health and pain comorbidities.
RESULTS: Our review found strong associations between NMPOU and the comorbidities of interest. Associations between NMPOU and mental health were strongest for depression (OR range 1.2 to 4.3) followed by anxiety disorders (OR range 1.2 to 3.0) in general and treatment populations. The prevalence of pain ranged from 14.5% to 61.5% in general, treatment, and street drug user samples reporting NMPOU.
CONCLUSIONS: The extensive associations observed between NMPOU and mental health and pain comorbidities suggest that effective preventive or treatment interventions for NMPOU must consider and attend to these comorbidities. As POAs are widely available and used in North America, POAs may increasingly be used in nonmedical ways for pain or mental health problems not effectively diagnosed or treated.

PMID: 21878161 [PubMed - indexed for MEDLINE]

Examining the role of mu opioid receptor endocytosis in the beneficial and side-effects of prolonged opioid use: From a symposium on new concepts in mu-opioid pharmacology.

Drug Alcohol Depend. 2012 Jan 5;

Authors: Whistler JL

Abstract
Opioid drugs remain the gold standard for the treatment of severe pain, both acute/post-surgical and chronic. However, the utility of opioid drugs for the treatment of chronic pain is compromised by the development of analgesic tolerance which, in turn, leads to dose-escalation and increased likelihood of dangerous side effects, including dependence. Consequently, there remains resistance among clinicians and the general population to using opiates for pain management because of risk of "addiction." These fears are not unwarranted. More than 2.5 million people begin abusing opioid painkillers each year, and prescription opioid abuse is now the second most common type of illegal drug use after marijuana. Some abusers become dependent due to recreational use of prescription painkillers. However, many abusers are among the 40 million people suffering from chronic pain, and developed dependence while using the drugs for legitimate purposes. Both of these trends highlight the need to develop opioid therapeutics with a reduced liability to cause tolerance, dependence and addiction. Identifying the ideal properties of opioid drugs that would retain analgesia but reduce these side-effects has been a goal of my laboratory for more than a decade. During this time, we have proposed the novel hypothesis that opioid drugs that promote desensitization, endocytosis and recycling of the mu-opioid-receptor (MOR) will retain analgesic efficacy, but will have a reduced liability to cause tolerance, dependence and addiction. We have generated substantial data, both pharmacological and genetic to suggest that our hypothesis is a valid one. These data are summarized in this review.

PMID: 22226706 [PubMed - as supplied by publisher]

ANALGESIA OR ADDICTION: IMPLICATIONS FOR MORPHINE USE AFTER SPINAL CORD INJURY.

J Neurotrauma. 2012 Jan 4;

Authors: Woller SA, Moreno GL, Hart N, Wellman PJ, Grau JW, Hook MA

Abstract
Opioid analgesics are one of the most effective treatments for neuropathic pain. However, the use of morphine after a spinal cord injury (SCI) can potentiate the development of paradoxical pain symptoms and continuous administration can lead to dependence, tolerance, and addiction. Although some studies suggest that the addictive potential of morphine decreases when it is used to treat neuropathic pain, this has not been studied in a SCI model. To address this issue, these studies investigated the addictive potential of morphine in a rodent model of SCI using conditioned place preference (CPP) and self-administration paradigms. A contusion injury significantly increased the expression of a CPP, relative to sham and intact controls in the acute phase of injury. However, contused animals self-administered significantly less morphine than sham and intact controls, but this was dose-dependent; at a high concentration, injured rats exhibited an increase in drug-reinforced responding over days. Exposure to a high concentration of morphine impeded weight gain and locomotor recovery. We suggest that the increased preference observed in injured rats reflects a motivational effect linked, in part, to the drug's antinociceptive effect. Further, although injured rats exhibited a suppression in opiate self-administration, when given access to a high concentration, addictive-like behavior emerged and was associated with poor recovery.

PMID: 22214368 [PubMed - as supplied by publisher]

Engineering endomorphin drugs: state of the art.

Expert Opin Ther Pat. 2012 Jan 4;

Authors: Lazarus LH, Okada Y

Abstract
Introduction: Although endomorphins-1 (EM-1; H-Tyr-Pro-Phe-Trp-NH(2)) and -2 (EM-2; H-Tyr-Pro-Phe-Phe-NH(2)) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties, suitable for application to health-related topics. While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimentally delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability; formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential. Areas covered: This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. Expert opinion: Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high-caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction.

PMID: 22214283 [PubMed - as supplied by publisher]

Characteristics of a nontreatment-seeking sample of over-the-counter codeine users: implications for intervention and prevention.

J Opioid Manag. 2011 Sep-Oct;7(5):363-70

Authors: Nielsen S, Cameron J, Lee N

Abstract
OBJECTIVES: Recently, there has been considerable policy and public interest in the availability of over-the-counter (OTC) codeine. Case reports demonstrating severe harm from OTC codeine have been published. However, few studies have examined how people use these products and who develops dependence. The aim of this study was to better understand who develops problematic use of OTC codeine.
DESIGN AND SETTING: The authors conducted a web-based survey with people who self-reported OTC codeine use. Eight hundred participants completed the survey that examined codeine use and dependence, pain, and general physical and mental health.
RESULTS: Codeine-dependent people differed from nondependent codeine users on a range of characteristics. They were younger, had lower levels of employment and education, and were more likely to report family history of substance dependence. They were more likely to have taken well above recommended doses of OTC codeine and have taken codeine for considerably longer periods of time than recommended. Codeine-dependent people in this study differed markedly from other populations of opioid-dependent people recruited to research in Australia and were more similar to the general population, suggesting that a web-based survey may have reached an under-researched population of opioid-dependent people.
CONCLUSIONS: How best to use these findings to identify at-risk OTC codeine users requires consideration. Approaches aimed at reducing harm from prescription opioids may be difficult to implement in pharmacy settings. Implications for pharmacists and other health professionals are discussed.

PMID: 22165035 [PubMed - in process]

Current Research on Opioid Receptor Function.

Curr Drug Targets. 2011 Dec 29;

Authors: Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y

Abstract
The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes are still widely unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as the some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The up-regulation of DOR expression and release of endogenous opioids increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.

PMID: 22204322 [PubMed - as supplied by publisher]

Identifying primary care skills and competencies in opioid risk management.

J Contin Educ Health Prof. 2011;31(4):231-40

Authors: Chiauzzi E, Trudeau KJ, Zacharoff K, Bond K

Abstract
INTRODUCTION: Primary care physicians (PCPs) treat a high proportion of chronic pain patients but often lack training about how to assess and address issues associated with prescribing opioids when they are an appropriate component of therapy. The result may be that they may avoid treating these patients, which can lead to an undertreatment of pain. The objective of this study was to identify which skills and competencies are most critical for PCPs in order to effectively manage opioid risk in patients treated for chronic pain.
METHODS: We conducted 1-hour interviews with 16 nationally known experts in primary care, pain management, and addiction. Eight were trained as PCPs, and 8 were trained as specialists. Their responses were collated and then presented online to the participants for independent sorting and rating. These data were analyzed using an online concept mapping program, which offers an innovative method of summarizing and prioritizing qualitative data.
RESULTS: Based on this analysis, items were organized into 10 clusters representing the most critical categories of skills (the "best fit" for these data). The cluster that received the highest average statement rating was "How to Manage Pain Patients With Comorbid Conditions." Follow-up analyses indicated that specialists rated this cluster, and 5 others, significantly higher than the PCPs, suggesting that the specialists perceive these competencies as more important in opioid risk management.
DISCUSSION: Using a relatively small sample and cost-effective technique (ie, concept mapping), key PCP competencies can be identified for potential inclusion in continuing education and training in opioid risk management.

PMID: 22189986 [PubMed - in process]

TH-030418: a potent long-acting opioid analgesic with low dependence liability.

Naunyn Schmiedebergs Arch Pharmacol. 2011 Aug;384(2):125-31

Authors: Yu G, Yan LD, Li YL, Wen Q, Dong HJ, Gong ZH

Abstract
Numerous efforts have been made on the chemical modification of opioid compounds, with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compounds, TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacological activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to μ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K (i) values of 0.56, 0.73, 0.60, and 1.55 nM, respectively. When administered subcutaneously, TH-030418 was much more potent than morphine in analgesia, with the ED(50) values of 1.37 μg/kg and 1.70 μg/kg in hot plate and acetic acid writhing tests, respectively. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addition, naloxone did not precipitate withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.

PMID: 21594658 [PubMed - in process]

Opiate addiction and prescription drug abuse: a pragmatic approach.

W V Med J. 2010;106(4 Spec No):84-5

Authors: Hasan KM, Hasan OK

PMID: 21932759 [PubMed - in process]

Signaling Cascades for Delta-opioid Receptor-mediated Inhibition of GABA Synaptic Transmission and Behavioral Antinociception.

Mol Pharmacol. 2011 Dec 5;

Authors: Zhang Z, Pan ZZ

Abstract
Membrane trafficking of the delta-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as chronic opioid exposure, represents unique receptor plasticity involved in the mechanisms of chronic opioid effects in opioid addiction and opioid treatment of chronic pain. However, the signaling pathways coupled to the newly emerged functional DOR in central neurons are largely unknown at present. In this study, we investigated the signaling cascades of chronic morphine-induced DOR for its cellular and behavioral effects in neurons of the rat brainstem nucleus raphe magnus (NRM), a key supraspinal site for opioid analgesia. We found that, among the three phospholipase A2 (PLA2)-regulated arachidonic acid (AA) metabolic pathways of lipoxygenase, cyclooxygenase and epoxygenase, 12-lipoxygenase of the lipoxygenase pathway primarily mediated DOR inhibition of GABA synaptic transmission, as inhibitors of 12-lipoxygenase as well as lipoxygenases and PLA2 largely blocked the DOR- or AA-induced GABA inhibition in NRM neurons in brainstem slices in vitro. Blockade of the epoxygenase pathway was ineffective whereas blocking either 5-lipoxygenase of the lipoxygenase pathway or the cyclooxygenase pathway enhanced the DOR-mediated GABA inhibition. Behaviorally in rats in vivo, NRM infusion of 12-lipoxygenase inhibitors significantly reduced DOR-induced antinociceptive effect while inhibitors of 5-lipoxygenase and cyclooxygenase augmented the DOR antinociception. These findings suggest the PLA2-CAA-C12-lipoxygenase pathway as a primary signaling cascade for DOR-mediated analgesia through inhibition of GABA neurotransmission and indicate potential therapeutic benefits of combining 5-lipoxygenase and cyclooxygenase inhibitors for maximal pain inhibition.

PMID: 22144670 [PubMed - as supplied by publisher]

Chronic pain, Addiction severity, and misuse of opioids in Cumberland County, Maine.

Addict Behav. 2011 Nov 20;

Authors: Heimer R, Dasgupta N, Irwin KS, Kinzly M, Harvey AP, Givens A, Grau LE

Abstract
BACKGROUND: Few studies have examined the relationship between chronic pain and opioid abuse in non-clinical populations. We sought to investigate this in a street-recruited sample of active opioid abusers in Cumberland County, Maine, USA, a locale that had experienced substantial increases in opioid abuse. METHODS: A community-based sample was recruited using respondent-driven sampling. Participants were screened to identify those who had consumed illicit opioids in the prior month and administered a structured survey that included the Addiction Severity Index (ASI) and Brief Pain Inventory® (BPI). RESULTS: More than 40% of the 237 individuals reported recurring pain that interfered with daily living. For more than three-quarters of those reporting chronic pain, opioid misuse preceded the onset of chronic pain. The order of onset was not associated with differences in sociodemographic, current levels of drug misuse, or ASI and BPI scores. BPI scores were associated with medical and psychological ASI domains. Compared to those not reporting chronic pain, those doing so were more likely to have a regular physician but were more likely to report difficulty gaining admission to substance abuse treatment programs. CONCLUSION: Chronic pain was a common co-occurring condition among individuals misusing opioids. Better efforts are needed to integrate pain management and substance abuse treatment for this population.

PMID: 22138379 [PubMed - as supplied by publisher]

Characterization of methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), two novel positive allosteric modulators of the GABAB receptor.

J Pharmacol Exp Ther. 2011 Nov 30;

Authors: Castelli MP, Casu A, Casti P, Lobina C, Carai MA, Colombo G, Solinas M, Giunta D, Mugnaini C, Pasquini S, Tafi A, Brogi S, Gessa GL, Corelli F

Abstract
The potential efficacy of GABA(B) receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA(B) receptor agonist, baclofen, considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA(B) receptor (GABA(B) PAMs) may constitute a novel approach in the pharmacological manipulation of the GABA(B) receptor leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), that act as GABA(B) PAMs in (a) rat cortical membranes, and (b) in vivo assay. Both compounds potentiated GABA- and baclofen-stimulated guanosine 5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPγS) binding to native GABA(B) receptors, whilst producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments (displacement of the GABA(B) receptor antagonist, [(3)H]CGP54626), both COR627 and COR628 increased the affinity of high- and low- affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of the positive allosteric modulatory binding sites of the GABA(B) receptor.

PMID: 22129594 [PubMed - as supplied by publisher]

Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: Alleviation by CRF(1) receptor antagonism.

Neuropharmacology. 2011 Nov 23;

Authors: Edwards S, Vendruscolo LF, Schlosburg JE, Misra KK, Wee S, Park PE, Schulteis G, Koob GF

Abstract
Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities.

PMID: 22119954 [PubMed - as supplied by publisher]