The μ opiate receptor as a candidate gene for pain: Polymorphisms, variations in expression, nociception, and opiate responses

There are differences between human individuals and between mouse strains in levels of μ opiate receptor (μOR) expression, responses to painful stimuli, and responses to opiate drugs. One of the best candidates for contributing to these differences is variation at the μOR gene locus. Support for this idea comes from analyses of the human and murine μOR genes. Assessments of individual differences in human μOR expression add further support. Studies with mice, including knockout-transgenic, quantitative trait locus, and strain-comparison studies, also strongly support the possibility that μOR gene alleles would be strong candidates for contributing to individual differences in human nociception and opiate drug responses. This paper reviews current analyses of the murine and human μOR genes, their important variants, and correlations between these variants and opiate influences on pain.

Children of substance-using mothers : child health engagement and child protection outcomes

Aim: Maternal substance use has been associated with a range of child risk factors. The study investigated the relationship between engagement with child health services and child protection outcomes for children of substance using mothers. ----- ----- Methods: A sample of 119 children of mothers who disclosed opiate, amphetamine or methadone use during a maternity admission between 2000 and 2003, as included in a previous matched co-hort study1, were included in the current study. Statutory child protection agency and child health engagement information for the first two years of life, was obtained. The relationship between type of maternal substance use, child health engagement and child protection outcomes was examined. ----- ----- Results: Seventy two percent of study group infants were engaged with child health services during the first two years of life. Chi square analysis showed no significant relationship between child health engagement and child protection reports. Child health engagement was associated with decreased substantiated child protection notifications for children of methadone using mothers, but not for children of illicit substance users. ----- ----- Conclusions: Almost a quarter of identified children of substance using mothers are not accessing standard child health services in their first two years of life. This study provides support for increased attention to the provision of child health services for children of methadone using mothers. Further research into effective intervention strategies for children of illicit substance using mothers is indicated.

A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia

Background A number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype. Methods To investigate the importance of this SNP in the function of DTNBP1, a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822. Results The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. Individuals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. Individuals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype. Conclusions This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

Postoperative pain relief using intermittent intrapleural analgesia following thoracoscopic anterior correction for progressive adolescent idiopathic scoliosis

Background Thoracoscopic anterior scoliosis instrumentation is a safe and viable surgical option for corrective fusion of progressive adolescent idiopathic scoliosis (AIS) and has been performed at our centre on 205 patients since 2000. However, there is a paucity of literature reporting on or examining optimum methods of analgesia following this type of surgery. A retrospective study was designed to present the authors’ technique for delivering intermittent local anaesthetic boluses via an intrapleural catheter following thoracoscopic scoliosis surgery; report the pain levels that may be expected and any adverse effects associated with the use of intrapleural analgesia, as part of a combined postoperative analgesia regime. Methods Records for 32 patients who underwent thoracoscopic anterior correction for AIS were reviewed. All patients received an intrapleural catheter inserted during surgery, in addition to patient-controlled opiate analgesia and oral analgesia. After surgery, patients received a bolus of 0.25% bupivacaine every four hours via the intrapleural catheter. Patient’s perceptions of their pain control was measured using the visual analogue pain scale scores which were recorded before and after local anaesthetic administration and the quantity and time of day that any other analgesia was taken, were also recorded. Results 28 female and four male patients (mean age 14.5 ± 1.5 years) had a total of 230 boluses of local anaesthetic administered in the 96 hour period following surgery. Pain scores significantly decreased following the administration of a bolus (p < 0.0001), with the mean pain score decreasing from 3.66 to 1.83. The quantity of opiates via patient-controlled analgesia after surgery decreased steadily between successive 24 hours intervals after an initial increase in the second 24 hour period when patients were mobilised. One intrapleural catheter required early removal due to leakage; there were no other associated complications with the intermittent intrapleural analgesia method. Conclusions Local anaesthetic administration via an intrapleural catheter is a safe and effective method of analgesia following thoracoscopic anterior scoliosis correction. Post-operative pain following anterior thoracic scoliosis surgery can be reduced to ‘mild’ levels by combined analgesia regimes. Keywords: Adolescent idiopathic scoliosis; Thoracoscopic anterior spinal fusion; Anterior fusion; Intrapleural analgesia; Endoscopic anterior surgery; Pain relief; Scoliosis surgery

Is intermittent intrapleural analgesia safe and effective following thoracoscopic anterior scoliosis correction surgery?

Introduction: Thoracoscopic anterior instrumented fusion (TASF) is a safe and viable surgical option for corrective stabilisation of progressive adolescent idiopathic scoliosis (AIS) [1-2]. However, there is a paucity of literature examining optimum methods of analgesia following this type of surgery. The aim of this study was to identify; if local anaesthetic bolus via an intrapleural catheter provides effective analgesia following thoracoscopic scoliosis correction; what pain levels may be expected; and any adverse effects associated with the use of intermittent intrapleural analgesia at our centre. Methods: A subset of the most recent 80 patients from a large single centre consecutive series of 201 patients (April 2000 to present) who had undergone TASF had their medical records reviewed. 32 patients met the inclusion criteria for the analysis (i.e. pain scores must have been recorded within the hour prior and within two hours following an intrapleural bolus being given). All patients received an intrapleural catheter inserted during surgery, in addition to patient-controlled opiate analgesia and oral analgesia as required. After surgery, patients received a bolus of 0.25% bupivacaine every four hours via the intrapleural catheter. Visual analogue pain scale scores were recorded before and after the bolus of local anaesthetic and the quantity and time of day that any other analgesia was taken, were also recorded. Results and Discussion: 28 female and four male patients (mean age 14.5 ± 1.5 years) had a total of 230 boluses of local anaesthetic administered intrapleurally, directly onto the spine, in the 96 hour period following surgery. Pain scores significantly decreased following the administration of a bolus (p<0.0001), with the mean pain score decreasing from 3.66 to 1.83. The quantity of opiates via patient-controlled analgesia after surgery decreased steadily between successive 24 hours intervals after an initial increase in the second 24 hour period when patients were mobilised. One intrapleural catheter required early removal at 26 hours postop due to leakage; there were no other associated complications with the intermittent intrapleural analgesia method. Post-operative pain following anterior scoliosis correction was decreased significantly with the administration of regular local anaesthetic boluses and can be reduced to ‘mild’ levels by combined analgesia regimes. The intermittent intrapleural analgesia method was not associated with any adverse events or complications in the full cohort of 201 patients.

A qualitative investigation of drug use among Pakistani road users

Background Statistics on drug use by Pakistani drivers are not available, yet considerable numbers of drivers are believed to be drug addicted. The National Drug Abuse Assessment 2006/07, conducted by the United Nation Office on Drugs and Crime and the Ministry of Narcotics Control Pakistan reported that opiate users numbered 628,000, of which 77%were chronic heroin abusers. Injecting drug users have reportedly doubled in the decade to 2006 and drug use has been linked with many major crashes involving professional drivers. Aims This study explored a broad range of risk taking behaviours of road users, including drug use. It also investigated associations between risky road use and fatalism and other cultural beliefs. Methods This paper reports findings relating to drug driving in the cities of Lahore, Rawalpindi and Islamabad. Thirty semi-structured interviews were conducted with bus, truck, and taxi drivers, policy makers and field police officers. Results Interviews suggested widespread use of illicit drugs, particularly among bus, truck and taxi drivers. Reasons for drug use included recreational purposes, stimulants during long driving episodes, and substance addiction. Furthermore, the use of drugs and any association with road crashes was generally viewed as linked to fatalism rather than to any fault of an individual. In other words, people did not believe there was an association between drug use and road crashes, even if they had personally experienced such. Police knowledge of drug use among drivers was evident, although there is no formal drug driving testing regime in Pakistan. Discussion and conclusions The substantial increase in drug use among the population in recent years highlights a significant public health challenge in Pakistan. This qualitative research, although recognized as not representative of the broader population, suggests that there is significant cause for concern about drug driving, especially among professional drivers, and a need for further investigation and intervention.

A commonly carried genetic variant in the delta opioid receptor gene, OPRD1, is associated with smaller regional brain volumes: Replication in elderly and young populations

Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.

Dysbindin (DTNBP1) variants are associated with hallucinations in schizophrenia

BACKGROUND: Dystrobrevin binding protein 1 (DTNBP1) is a schizophrenia susceptibility gene involved with neurotransmission regulation (especially dopamine and glutamate) and neurodevelopment. The gene is known to be associated with cognitive deficit phenotypes within schizophrenia. In our previous studies, DTNBP1 was found associated not only with schizophrenia but with other psychiatric disorders including psychotic depression, post-traumatic stress disorder, nicotine dependence and opiate dependence. These findings suggest that DNTBP1 may be involved in pathways that lead to multiple psychiatric phenotypes. In this study, we explored the association between DTNBP1 SNPs (single nucleotide polymorphisms) and multiple psychiatric phenotypes included in the Diagnostic Interview of Psychosis (DIP). METHODS: Five DTNBP1 SNPs, rs17470454, rs1997679, rs4236167, rs9370822 and rs9370823, were genotyped in 235 schizophrenia subjects screened for various phenotypes in the domains of depression, mania, hallucinations, delusions, subjective thought disorder, behaviour and affect, and speech disorder. SNP-phenotype association was determined with ANOVA under general, dominant/recessive and over-dominance models. RESULTS: Post hoc tests determined that SNP rs1997679 was associated with visual hallucination; SNP rs4236167 was associated with general auditory hallucination as well as specific features including non-verbal, abusive and third-person form auditory hallucinations; and SNP rs9370822 was associated with visual and olfactory hallucinations. SNPs that survived correction for multiple testing were rs4236167 for third-person and abusive form auditory hallucinations; and rs9370822 for olfactory hallucinations. CONCLUSION: These data suggest that DTNBP1 is likely to play a role in development of auditory related, visual and olfactory hallucinations which is consistent with evidence of DTNBP1 activity in the auditory processing regions, in visual processing and in the regulation of glutamate and dopamine activity

Medicalising Prohibition : Harm reduction in Finnish and International Drug Policy

The increase in drug use and related harms in the late 1990s in Finland has come to be referred to as the second drug wave. In addition to using criminal justice as a basis of drug policy, new kinds of drug regulation were introduced. Some of the new regulation strategies were referred to as "harm reduction". The most widely known practices of harm reduction include needle and syringe exchange programmes for intravenous drug users and medicinal substitution and maintenance treatment programmes for opiate users. The purpose of the study is to examine the change of drug policy in Finland and particularly the political struggle surrounding harm reduction in the context of this change. The aim is, first, to analyse the content of harm reduction policy and the dynamics of its emergence and, second, to assess to what extent harm reduction undermines or threatens traditional drug policy. The concept of harm reduction is typically associated with a drug policy strategy that employs the public health approach and where the principal focus of regulation is on drug-related health harms and risks. On the other hand, harm reduction policy has also been given other interpretations, relating, in particular, to human rights and social equality. In Finland, harm reduction can also be seen to have its roots in criminal policy. The general conclusion of the study is that rather than posing a threat to a prohibitionist drug policy, harm reduction has come to form part of it. The implementation of harm reduction by setting up health counselling centres for drug users with the main focus on needle exchange and by extending substitution treatment has implied the creation of specialised services based on medical expertise and an increasing involvement of the medical profession in addressing drug problems. At the same time the criminal justice control of drug use has been intensified. Accordingly, harm reduction has not entailed a shift to a more liberal drug policy nor has it undermined the traditional policy with its emphasis on total drug prohibition. Instead, harm reduction in combination with a prohibitionist penal policy constitutes a new dual-track drug policy paradigm. The study draws on the constructionist tradition of research on social problems and movements, where the analysis centres on claims made about social problems, claim-makers, ways of making claims and related social mobilisation. The research material mainly consists of administrative documents and interviews with key stakeholders. The doctoral study consists of five original articles and a summary article. The first article gives an overview of the strained process of change of drug policy and policy trends around the turn of the millennium. The second article focuses on the concept of harm reduction and the international organisations and groupings involved in defining it. The third article describes the process that in 1996 97 led to the creation of the first Finnish national drug policy strategy by reconciling mutually contradictory views of addressing the drug problem, at the same as the way was paved for harm reduction measures. The fourth article seeks to explain the relatively rapid diffusion of needle exchange programmes after 1996. The fifth article assesses substitution treatment as a harm reduction measure from the viewpoint of the associations of opioid users and their family members.

Increased opioid dependence in a mouse model of panic disorder

[EN] Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

Frontal and cingulate gray matter volume reduction in heroin dependence: Optimized voxel-based morphometry

Aims: Repeated exposure to heroin, a typical opiate, causes neuronal adaptation and may result in anatomical changes in specific brain regions, particularly the frontal and limbic cortices. The volume changes of gray matter (GM) of these brain regions, ho

阿片类药物成瘾者瞳孔光反射的检测和特征提取

建立了一种基于图像处理的快速瞳孔直径检测算法,运用此算法提取了反映阿片类药物成瘾人员与正常人对瞳孔光反射变化差异的3个特征值:绝对收缩幅度(absolute amplitude of contraction,AAC)、相对收缩幅度(relative amplitude of contraction,RAC)和收缩斜率(SCV,slope of contraction velocity);分别研究了成瘾、性别、近视、年龄、睡眠剥夺等因素对于这3个特征值的影响。不同性别、近视人员、睡眠剥夺人员与正常人之间的3个特征值均无显著差异,成瘾人员与之对比均显著减小。老年人相对于正常青年人,3个特征值都明显减小;与成瘾人员相比,仅在RAC值上有显著差异。结果表明,阿片类药物成瘾人员除了与正常人外,也与其他具有潜在影响瞳孔变化因素的非阿片成瘾人员在瞳孔对光反射的特征值上具有显著差异。该研究的实验数据为进一步建立基于检测瞳孔对光反射其直径发生变化的方法来快速、非接触地鉴别出阿片类药物成瘾人员提供了可靠的依据。