Synergistic interactions between cannabinoid and opioid analgesics

Cannabinoids and opioids both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects. Thus, a search for a better analgesic strategy led to the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, enhances the potency of opioids such as morphine in animal models. In addition, studies have determined that the analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception. A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia, and some of these findings are presented below. The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.     

Trends in breast cancer mortality in Sweden before and after implementation of mammography screening

Background

Incidence-based mortality modelling comparing the risk of breast cancer death in screened and unscreened women in nine Swedish counties has suggested a 39% risk reduction in women 40 to 69 years old after introduction of mammography screening in the 1980s and 1990s.

Objective

We evaluated changes in breast cancer mortality in the same nine Swedish counties using a model approach based on official Swedish breast cancer mortality statistics, robust to effects of over-diagnosis and treatment changes. Using mortality data from the NordCan database from 1974 until 2003, we estimated the change in breast cancer mortality before and after introduction of mammography screening in at least the 13 years that followed screening start.

Results

Breast mortality decreased by 16% (95% CI: 9 to 22%) in women 40 to 69, and by 11% (95% CI: 2 to 20%) in women 40 to 79 years of age.

Discussion

Without individual data it is impossible to completely separate the effects of improved treatment and health service organisation from that of screening, which would bias our results in favour of screening. There will also be some contamination of post-screening mortality from breast cancer diagnosed prior to screening, beyond our attempts to adjust for delayed benefit. This would bias against screening. However, our estimates from publicly available data suggest considerably lower benefits than estimates based on comparison of screened versus non-screened women.     

Comparison of the ability of opioid analgesics to increase endogenous opioid-like activity in the cerebrospinal fluid of rabbits

We have previously demonstrated that the acute administration of morphine increases the level of endogenous substances, which have antinociceptive activity, in cerebrospinal fluid (CSF). The present study was conducted to determine whether other opioid analgesics exert a similar effect. CSF was withdrawn from the cisterna magna of anesthetized rabbits before and after s.c. injections of meperidine, pentazocine, levorphanol and methadone, and was bioassayed for opioid-like activity in the mouse tail-flick and phenylquinone writhing tests. The opioid-like activity of CSF taken 60 min after meperidine (50 mg/kg) was significantly increased in both bioassays, and the CSF level of meperidine was insufficient to account for this effect. Pentazocine (25-75 mg/kg) also significantly increased opioid-like activity in rabbit CSF, but the effects of methadone (5-10 mg/kg) and levorphanol (20 mg/kg) were less marked. Dextrorphan (20 mg/kg), diazepam (10 mg/kg) and pentobarbital (20 mg/kg) administration did not significantly increase opioid-like activity in CSF. It is concluded that the antinociceptive action of some opioid analgesics in rabbits may be mediated in part by the release of endogenous antinociceptive substances.     

Reduction and recovery of keystone predation pressure after disease‐related mass mortality

Disturbances such as disease can reshape communities through interruption of ecological interactions. Changes to population demographics alter how effectively a species performs its ecological role. While a population may recover in density, this may not translate to recovery of ecological function. In 2013, a sea star wasting syndrome outbreak caused mass mortality of the keystone predator Pisaster ochraceus on the North American Pacific coast. We analyzed sea star counts, biomass, size distributions, and recruitment from long‐term intertidal monitoring sites from San Diego to Alaska to assess regional trends in sea star recovery following the outbreak. Recruitment, an indicator of population recovery, has been spatially patchy and varied within and among regions of the coast. Despite sea star counts approaching predisease numbers, sea star biomass, a measure of predation potential on the mussel Mytilus californianus, has remained low. This indicates that post‐outbreak populations have not regained their full predation pressure. The regional variability in percent of recovering sites suggested differences in factors promoting sea star recovery between regions but did not show consistent patterns in postoutbreak recruitment on a coast‐wide scale. These results shape predictions of where changes in community composition are likely to occur in years following the disease outbreak and provide insight into how populations of keystone species resume their ecological roles following mortality‐inducing disturbances.     

Genomewide linkage scan for opioid dependence and related traits

Risk of opioid dependence is genetically influenced. We recruited a sample of 393 small nuclear families (including 250 full-sib and 46 half-sib pairs), each with at least one individual with opioid dependence. Subjects underwent a detailed evaluation of substance dependence-related traits. As planned a priori to reduce heterogeneity, we used cluster analytic methods to identify opioid dependence-related symptom clusters, which were shown to be heritable. We then completed a genomewide linkage scan (with 409 markers) for the opioid-dependence diagnosis and for the two cluster-defined phenotypes represented by >250 families: the heavy-opioid-use cluster and the non-opioid-use cluster. Further exploratory analyses were completed for the other cluster-defined phenotypes. The statistically strongest results were seen with the cluster-defined traits. For the heavy-opioid-use cluster, we observed a LOD score of 3.06 on chromosome 17 (empirical pointwise P = .0002) for European American (EA) and African American (AA) subjects combined, and, for the non-opioid-use cluster, we observed a LOD score of 3.46 elsewhere on chromosome 17 (empirical pointwise P = .00002, uncorrected for multiple traits studied) for EA subjects only. We also identified a possible linkage (LOD score 2.43) of opioid dependence with chromosome 2 markers for the AA subjects. These results are an initial step in identifying genes for opioid dependence on the basis of a genomewide investigation (i.e., a study not conditioned on prior physiological candidate-gene hypotheses).     

Job stress,satisfaction, and mental health among general practitioners before and after introduction of new contract.

OBJECTIVE--To compare measures of job stress, job satisfaction, and mental health among general practitioners before and after the introduction of the new contract in April 1990. DESIGN--Cross sectional postal questionnaire survey in July 1990. Comparison of results with those obtained in previous survey in November 1987. SETTING--General practice in United Kingdom. SUBJECTS--1500 general practitioners randomly selected from general medical services lists, 917 of whom (61%) returned questionnaires usable for statistical analysis. MAIN OUTCOME MEASURES--Aspects of job causing stress, job satisfaction (Warr, Cook, and Wall scale), and mental health (Crown-Crisp experiential index). RESULTS--Compared with 1987, in 1990 doctors experienced more stress from night calls (mean score 3.83 in 1990 v 3.45 in 1987), emergencies during surgery hours (3.72 v 3.48), and interruption of family life by telephone (3.58 v 2.73; p less than 0.001 for all three variables). Scores for somatic anxiety and depression were higher in both men and women in 1990 (men: somatic anxiety 3.12 v 2.36; depression 3.80 v 2.94; women: somatic anxiety 3.56 v 2.65; depression 4.02 v 3.37; p less than 0.001). Job satisfaction had also decreased in 1990 (5.23 v 4.26; p less than 0.001). CONCLUSIONS--Doctors experienced more stress, less job satisfaction, and poorer mental health in 1990 than in 1987. These changes may have resulted from the introduction of the new contract.     

Effect of cerebrocrast, a new long-acting compound on blood glucose and insulin levels in rats when administered before and after STZ-induced diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin secreting pancreatic islets beta-cells. The formation of cytokines (IL-1beta, IL-6, TNF-alpha, etc.) leads to extensive morphological damage of beta-cells, DNA fragmentation, decrease of glucose oxidation, impaired glucose-insulin secretion and decreased insulin action and proinsulin biosynthesis. We examined the protective effect of a 1,4-dihydropyridine (DHP) derivative cerebrocrast (synthesized in the Latvian Institute of Organic Synthesis) on pancreatic beta-cells in rats possessing diabetes induced with the autoimmunogenic compound streptozotocin (STZ). Cerebrocrast administration at doses of 0.05 and 0.5 mg/kg body weight (p.o.) 1 h or 3 days prior to STZ as well as at 24 and 48 h after STZ administration partially prevented pancreatic beta-cells from the toxic effects of STZ, and delayed the development of hyperglycaemia. Administration of cerebrocrast starting 48 h after STZ-induced diabetes in rats for 3 consecutive days at doses of 0.05 and 0.5 mg/kg body weight (p.o.) significantly decreased blood glucose level, and the effect remained 10 days after the last administration. Moreover, in these rats, cerebrocrast evoked an increase of serum immunoreactive insulin (IRI) level during 7 diabetic days as compared to both the control normal rats and the STZ-induced diabetic control rats. The STZ-induced diabetic rats that received cerebrocrast had a significantly high serum IRI level from the 14th to 21st diabetic days in comparison with the STZ-induced diabetic control.The IRI level in serum as well as the glucose disposal rate were significantly increased after stimulation of pancreatic beta-cells with glucose in normal rats that received cerebrocrast, administered 60 min before glucose. Glucose disposal rate in STZ-induced diabetic rats as a result of cerebrocrast administration was also increased in comparison with STZ-diabetic control rats. Administration of cerebrocrast in combination with insulin intensified the effect of insulin. The hypoglycaemic effect of cerebrocrast primarily can be explained by its immunomodulative properties. Moreover, cerebrocrast can act through extrapancreatic mechanisms that favour the expression of glucose transporters, de novo insulin receptors formation in several cell membranes as well as glucose uptake.     

Effectiveness of a regional trauma system in reducing mortality from major trauma: before and after study.

OBJECTIVE: To assess the effect of the development of an experimental trauma centre and regional trauma system on the survival of patients with major trauma. DESIGN: Controlled before and after study examining outcomes between 1990 and 1993, spanning the introduction of the system in 1991-2. SETTING: Trauma centre in North Staffordshire Royal Infirmary and five associated district general hospitals in the North West Midlands regional trauma system, and two control regions in Lancashire and Humberside. SUBJECTS: All trauma patients taken by the ambulance services serving the regions or arriving other than by ambulance with injury severity scores > 15, whether or not they had vital signs on arrival at hospital. MAIN OUTCOME MEASURES: Survival rates standardised for age, severity of injury, and revised trauma score. RESULTS: In 1990, 33% of major trauma patients in the experimental region were taken to the trauma centre, and by 1993 this had risen to only 39%. Crude death rates changed by the same amount in the control regions (46.5% in 1990-1 to 44.4% in 1992-3) as in the experimental region (44.8% to 41.3%). After standardisation, the estimated change in the probability of dying in the experimental region compared with the control regions was -0.8% per year (95% confidence interval -3.6% to 2.2%); for out of hours care, the change was 1.6% per year (-2.3% to 5.6%), and, for multiply injured patients, the change was -1.6% (-6.1% to 2.6%). CONCLUSION: Any reductions in mortality from regionalising major trauma care in shire areas of England would probably be modest compared with reports from the United States.