The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB₂). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB₂ is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB₂ receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB₂ agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.

BackgroundSmad-interacting protein 1 (also named Zeb2 and Zfhx1b) is a transcription factor that plays an important role in neuronal development and, when mutated, causes Mowat-Wilson syndrome (MWS). A corresponding mouse model carrying a heterozygous Zeb2 deletion was comprehensively analysed in the German Mouse Clinic. The most prominent phenotype was the reduced pain sensitivity. In this study, we investigated the role of Zeb2 in inflammatory and neuropathic pain.MethodsFor this, we tested mutant Zeb2 animals in different models of inflammatory pain like abdominal constriction, formalin and carrageenan test. Furthermore, we studied the pain reactivity of the mice after peripheral nerve ligation. To examine the nociceptive transmission of primary sensory dorsal root ganglia (DRG) neurons, we determined the neuronal activity in the spinal dorsal horn after the formalin test using staining of c-Fos. Next, we characterized the neuronal cell population in the DRGs and in the sciatic nerve to study the effect of the Zeb2 mutation on peripheral nerve morphology.ResultsThe present data show that Zeb2 is involved in the development of primary sensory DRG neurons, especially of C- and A fibres. These alterations contribute to a hypoalgesic phenotype in inflammatory but not in neuropathic pain in these Zeb2(+/-) mice.ConclusionOur data suggest that the under-reaction to pain observed in MWS patients results from a reduced responsivity to nociceptive stimulation rather than an inability to communicate discomfort.

# S15.1 DYREGULATED LEPTIN LEVELS IN HEAVY DRINKING ALCOHOL-DEPENDENT SUBJECTS AND THE LOSS OF METABOLIC CONTROL {#article-title-2} Background. Most physiological studies of alcoholism consider ethanol as a pharmacological agent rather than a nutrient. We conducted two studies to assess potent metabolic and endocrine factors of alcohol and nutrient intake regulation in alcoholic subjects and a possible role of a disruption of energy balance for the development of alcoholism. Methods and results: Study-1 consists of quantitative anamneses of eating and drinking habits among 97 alcoholics. The population was split around a median alcohol intake value of 12.5 kcal/kg/day. “Low alcohol” drinking alcoholics had high BMI and Fat Mass (FM) and alcohol intake was compensated for by a decrease in non-alcoholic intake. “High alcohol” drinking alcoholics had low BMI and FM and the total intake was largely above norms. In Study-2, 22 alcoholic inpatients submitted on day 2, 5 and 16 of abstinence to diet anamneses, calorymetry, and blood sampling for the measurement of biomarkers reflecting metabolism and satiety regulation were compared to 19 matched controls. We observed increased cortisol, leptin and PYY plasma levels and decreased plasma ghrelin, that might explain the observed decrease in non-alcoholic intake. However, both alcoholic and non-alcoholic intake correlated positively with basal metabolism and negatively with leptin and leptin/BMI. Conclusion. Below12.5kcal/kg/day, alcohol intake is compensated for by a decrease in nutrient intake, probably due to changes in metabolic and satiety factors. Above 12.5kcal/kg/day, alcohol accelerates metabolism and decreases fat mass and leptin levels, and the total intake largely exceeds norms. A dual model for regulation of energy intake in alcoholics is suggested. # S15.2 THE ASSOCIATION OF THE APPETITIVE PEPTIDE ACETYLATED GHRELIN WITH ALCOHOL CRAVING IN EARLY ABSTINENT ALCOHOL DEPENDENT INDIVIDUALS {#article-title-3} Objective. Preclinical studies provided support for an important role of ghrelin in the neurobiology of alcohol dependence. In contrast, clinical data have until now failed to support an association between ghrelin and alcohol craving. Materials and Methods. We assessed plasma concentrations of both active and total ghrelin in a sample of 61 alcohol-dependent male inpatients, using blood samples taken at the onset of withdrawal and after 14 days of controlled abstinence. During this time, we also assessed the patients' alcohol cravings (applying the obsessive compulsive drinking scale, or OCDS), symptoms of depression (Beck Depression Inventory; BDI) and anxiety (State Trait Anxiety Inventory; STAI). The severity of alcohol dependence was assessed using the alcohol dependence scale (ADS). Results. We found a significant positive correlation between the plasma concentration of active ghrelin and alcohol craving in both blood samples. Plasma concentrations of active ghrelin increased significantly during early abstinence. In a linear regression model, the plasma concentration of active ghrelin on day one, the scores of the ADS, and the BDI explained 36% of the variance in OCDS sum score (p < 0.0001). By day 14, these same factors accounted for 54% (p < 0.0001). We did not detect any association between the plasma concentration of total ghrelin and patients' alcohol cravings. Conclusion. Our results suggest that biologically active ghrelin is involved in reward-associated craving during early abstinence. Antagonizing ghrelin at its central growth-hormone secretagogue receptors (GHS-R1A) in the ventral tegmental area (VTA) may be a novel pharmacological target in the treatment for craving in alcoholics. # S15.3 LONG-TERM ETHANOL EFFECTS ON ACUTE STRESS RESPONSES {#article-title-4} The brain stress-response system is critically involved in the addiction process, stimulating drug consumption and the relapse to drug taking in abstinent addicts. At the same time, its functioning is affected by chronic drug exposure. Here, we have investigated the role of the endogenous opioid peptide dynorphin as a modulator of effects of long-term ethanol consumption on the brain stress-response system. Using the two-bottle choice paradigm we demonstrate an enhanced ethanol preference in male dynorphin knockout mice. Exposure to mild foot shock increased ethanol consumption in wild type control littermates, but not in dynorphin deficient animals. Blood ACTH levels determined 5 minutes after the shock were not affected by the genotype. We also determined the neuronal reactivity after foot shock exposure using c-Fos immunoreactivity in limbic structures. This was strongly influenced by both genotype and chronic ethanol consumption. Together these data suggest that dynorphin plays an important role in the modulation of the brain stress-response systems after chronic ethanol exposure. # S15.4 ACUTE ETHANOL EFFECTS ON THE HYPOTHALAMIC-PITUITARY-ADRENAL SYSTEM IN HEALTHY SUBJECTS {#article-title-5} Background. Acute alcohol challenge studies in rodents and naturalistic observations in drinking alcoholics suggest that alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) system. The literature on respective studies in healthy volunteers is more inconsistent, suggesting differential alcohol effects depending on dosage, recent drinking history, family history of alcoholism, and alcohol-induced side effects. Methods. We investigated how secretion of adrenocorticotrophin (ACTH) and cortisol are affected by ingestion of 0.6 g/kg ethanol in 33 young healthy socially drinking males with a paternal history of alcoholism (PHP) vs. 30 with a negative family history (FHN). Alcohol and placebo were administered in a two-days, double-blind, placebo controlled crossover design with randomized administration sequence. Results. After administration of placebo, ACTH and cortisol decreased steadily over 130 minutes. In FHN subjects, secretion of both hormones was even more attenuated after alcohol, resulting in significantly lower levels compared to placebo. In PHP subjects, no alcohol effect on hormone secretion could be detected. The ratio of cortisol to ACTH secretion, each expressed as area under the secretion curve, was significantly increased by alcohol in FHN and PHP participants. Conclusions. These results argue against HPA stimulation being a mechanism that promotes the transition from moderate to dependent drinking. The fact that alcohol-induced HPA suppression was not detected in PHP males is consistent with the general concept that subjects at high risk for alcoholism exhibit less pronounced alcohol effects.

European Journal of Pain SupplementsVolume 4, Issue S1 p. 57-57 194 EFFECTS OF A NATURAL CB2 RECEPTOR AGONIST IN NEUROPATHIC PAIN I. Rácz, I. Rácz Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this authorA.-L. Klauke, A.-L. Klauke Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this authorA. Markert, A. Markert Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this authorJ. Gertsch, J. Gertsch Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule, Zürich, SwitzerlandSearch for more papers by this authorA. Zimmer, A. Zimmer Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this author I. Rácz, I. Rácz Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this authorA.-L. Klauke, A.-L. Klauke Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this authorA. Markert, A. Markert Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this authorJ. Gertsch, J. Gertsch Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule, Zürich, SwitzerlandSearch for more papers by this authorA. Zimmer, A. Zimmer Institute of Molecular Psychiatry, University of Bonn, Bonn, GermanySearch for more papers by this author First published: 06 January 2012 https://doi.org/10.1016/S1754-3207(10)70199-1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume4, IssueS1April 2010Pages 57-57 RelatedInformation