Janus molecule I: dichotomous effects of COMT in neuropathic vs nociceptive pain modalities.

The enzyme catechol-O-methyltransferase (COMT) has been shown to play a critical role in pain perception by regulating levels of epinephrine (Epi) and norepinephrine (NE). Although the key contribution of catecholamines to the perception of pain has been recognized for a long time, there is a clear dichotomy of observations. More than a century of research has demonstrated that increasing adrenergic transmission in the spinal cord decreases pain sensitivity in animals. Equally abundant evidence demonstrates the opposite effect of adrenergic signaling in the peripheral nervous system, where adrenergic signaling increases pain sensitivity. Viewing pain processing within spinal and peripheral compartments and determining the directionality of adrenergic signaling helps clarify the seemingly contradictory findings of the pain modulatory properties of adrenergic receptor agonists and antagonists presented in other reviews. Available evidence suggests that adrenergic signaling contributes to pain phenotypes through α(1/2) and ß(2/3) receptors. While stimulation of α(2) adrenergic receptors seems to uniformly produce analgesia, stimulation of α(1) or ß receptors produces either analgesic or hyperalgesic effects. Establishing the directionality of adrenergic receptor modulation of pain processing, and related COMT activity in different pain models are needed to bring meaning to recent human molecular genetic findings. This will enable the translation of current findings into meaningful clinical applications such as diagnostic markers and novel therapeutic targets for complex human pain conditions.

COMT genetic variants and pain.

Catechol-O-methyltransferase (COMT) metabolizes catechol neurotransmitters dopamine, noradrenaline and adrenaline that are involved in various physiological functions including mood, cognition and stress response. Human pain is closely related to all these functions. The gene encoding the COMT enzyme (COMT) has functional polymorphisms that contribute to the interindividual variability in human pain phenotypes such as pain sensitivity, chronicity, severity and response to pain medicine. This review outlines pain symptoms and syndromes that are affected by COMT functional variation, summarizes findings of genetic association studies and provides critical outlook on reported results. Although the exact mechanism of the effect of COMT on human pain is currently uncertain, it has a clear potential to predict clinical outcomes and identify patients at risk for developing pain conditions.

Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study.

BACKGROUND: Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated. METHOD: In the present study, a genome-wide linkage scan for nicotine dependence was conducted in a community sample of 950 probands and 1204 relatives recruited through the University of California, San Francisco (UCSF) Family Alcoholism Study. A modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) with additional questions that probe nicotine use was used to derive DSM-IV nicotine dependence diagnoses. RESULTS: A locus on chromosome 2q31.1 at 184 centiMorgans nearest to marker D2S2188 yielded a logarithm (base 10) of odds (LOD) score of 3.54 (point-wise empirical p=0.000012). Additional peaks of interest were identified on chromosomes 2q13, 4p15.33-31, 11q25 and 12p11.23-21. Follow-up analyses were conducted examining the contributions of individual nicotine dependence symptoms to the chromosome 2q31.1 linkage peak as well as examining the relationship of this chromosomal region to alcohol dependence. CONCLUSIONS: The present report suggests that chromosome 2q31.1 confers risk to the development of nicotine dependence and that this region influences a broad range of nicotine dependence symptoms rather than a specific facet of the disorder. Further, the results show that this region is not linked to alcohol dependence in this population, and thus may influence nicotine dependence specifically.

Comt1 genotype and expression predicts anxiety and nociceptive sensitivity in inbred strains of mice.

Catechol-O-methyltransferase (COMT) is a ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catechol substrates. In humans, polymorphic variance at the COMT locus has been associated with modulation of pain sensitivity and risk for developing psychiatric disorders. A functional haplotype associated with increased pain sensitivity was shown to result in decreased COMT activity by altering mRNA secondary structure-dependent protein translation. However, the exact mechanisms whereby COMT modulates pain sensitivity and behavior remain unclear and can be further studied in animal models. We have assessed Comt1 gene expression levels in multiple brain regions in inbred strains of mice and have discovered that Comt1 is differentially expressed among the strains, and this differential expression is cis-regulated. A B2 short interspersed nuclear element (SINE) was inserted in the 3'-untranslated region (3'-UTR) of Comt1 in 14 strains generating a common haplotype that correlates with gene expression. Experiments using mammalian expression vectors of full-length cDNA clones with and without the SINE element show that strains with the SINE haplotype (+SINE) have greater Comt1 enzymatic activity. +SINE mice also exhibit behavioral differences in anxiety assays and decreased pain sensitivity. These results suggest that a haplotype, defined by a 3'-UTR B2 SINE element, regulates Comt1 expression and some mouse behaviors.

Analgesia during extracorporeal shock wave lithotripsy using the Medstone STS lithotriptor: a randomized prospective study.

OBJECTIVES: To investigate and compare the effectiveness of three analgesic protocols for pain management during extracorporeal shock wave lithotripsy (ESWL) in a prospective, randomized clinical trial. METHODS: Seventy-four patients were randomized into three groups before ESWL; group A (n = 23) received 10 mg morphine sulfate (MS), group B (n = 25) 60 mg ketorolac tromethamine (KT), and group C (n = 26) topical 2.5% lidocaine/prilocaine gel (Emla). Each method of pain management during ESWL was assessed using a standard 10-point linear pain scale and by the requirement for supplemental analgesia during treatment. Supplemental analgesia was administered intravenously using a patient-controlled analgesic pump. The results were compared between the three groups, as were such parameters as body habitus, stone burden, stone location, number of shock waves, and the presence of ureteral stents. RESULTS: Pain severity averaged 4.6 points on the pain scale for the three groups combined. Pain tended to be more severe in group C (5.4) than in group A (4.3) or group B (4.1); however, the differences were not statistically significant (P>0.05). The amount of supplemental analgesia was similar in all three groups. Stone burden, stone location, and number of shock waves did not influence the severity of pain or analgesic requirement during ESWL. The analgesic requirement was significantly less in patients with ureteral stents (n = 32) than in patients without (n = 42), averaging 10 mg versus 24 mg MS, respectively (P = 0.01). KT was not associated with adverse events such as bleeding. MS was more likely to cause oversedation and nausea or vomiting, necessitating naloxone and antiemetic therapy, respectively. CONCLUSIONS: The use of KT was safe and effective for premedication before ESWL; patients receiving KT before ESWL reported lower pain scores and required less supplemental analgesia requirement than those who received MS or Emla; however, the differences were not statistically significant. Patients receiving Emla recorded the highest pain scores. Patients with ureteral stents had lower pain scores and required less supplemental analgesia.

Wheat bran decreases aberrant crypt foci, preserves normal proliferation, and increases intraluminal butyrate levels in experimental colon cancer.

BACKGROUND: Dietary wheat bran protects against colon cancer, but the mechanism(s) of this effect is not known. Butyrate, produced by colonic bacterial fermentation of dietary polysaccharides, such as wheat bran, induces apoptosis and decreases proliferation in colon cancer cell lines. Whether similar effects occur in vivo is not well defined. We hypothesized that wheat bran's antineoplastic effects in vivo may be mediated in part by butyrate's modulation of apoptosis and proliferation. METHODS: Male F344 rats were fed wheat bran-supplemented or an isocaloric, isonitrogenous fiber-free diet. Rats were treated with one dose of the carcinogen azoxymethane or vehicle with sacrifice after 5 days (tumor initiation); or two doses (days O and 7) with sacrifice after 56 days (tumor promotion). Study variables included fecal butyrate levels and the intermediate biomarkers of colon carcinogenesis, aberrant crypt foci (ACF), and changes in crypt cell proliferation and apoptosis. RESULTS: During tumor initiation, wheat bran produced greater apoptosis (p = .01), a trend toward less proliferation, and preserved the normal zone of proliferation (p = .01). At tumor promotion, wheat bran decreased the number of ACF (proximal colon, p = .005; distal colon, p = .047) and maintained the normal proliferative zone. The fiber-free diet shifted the zone of proliferation into the premalignant pattern in both studies. Wheat bran produced significantly higher fecal butyrate (p = .01; .004, .00001) levels than the fiber-free diet throughout the tumor promotion study. CONCLUSIONS: Wheat bran increased apoptosis and controlled proliferation during tumor initiation and resulted in decreased ACF. Wheat bran's antineoplastic effects occurred early after carcinogen exposure, and were associated with increased fecal butyrate levels.