Pain modality- and sex-specific effects of COMT genetic functional variants

The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to inter-individual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality-specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3’UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female versus male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics

The bee venom test : a new tonic-pain test

The present study describes a new test of tonic pain in rats which can be used as an animal model of persistent pain. In the first experiment, the response to subcutaneous injection of various doses of bee venom into the hind paw of the rat was quantified. The second experiment investigated the effect of morphine and aspirin on the response to an intermediate dose of bee venom. Finally, the third experiment examined the response to concurrent injections of bee venom and formalin. Subcutaneous injection of bee venom produced local inflammation, marked edema, and tonic pain responses. Increasing doses of bee venom produced higher mean pain scores and increased durations of responding. Pain responses lasted up to approximately one hour and the inflammation and edema were virtually gone by 8 hours with the lower doses of bee venom tested and by 2 days with the two highest doses tested. Analgesia was produced by morphine and aspirin, indicating that the bee venom test can be used to test analgesic drugs. Concurrent administration of bee venom and formalin produced responses similar to formalin alone, with an increased duration of responding at higher intensities. The data suggest that the bee venom test is a valid animal model of experimental tonic pain

The role of the hypothalamic-pituitary-adrenal axis in the susceptibility to adjuvant-induced polyarthritis in the rat /

The hypothalamic-pituitary-adrenal (HPA) axis, a system activated by stress, is traditionally considered to affect the susceptibility to chronic pain via effects on peripheral processes. This study investigates whether the HPA axis contributes to the development of chronic pain in an animal model via direct effects on central pain mechanisms.First, correlations between pain processes and the susceptibility to chronic pain in an animal model that is correlated with HPA-axis function were examined. The results show that, in the Fischer rat, the amount of pain suppression observed during the formalin interphase depression is negatively correlated with susceptibility to polyarthritis. Since the formalin interphase depression mechanisms are within the central nervous system, the results suggest a role for central pain mechanisms in the development of polyarthritis.Hypophysectomy inhibits the development of adjuvant-induced arthritis. To test whether hypophysectomy inhibits adjuvant-induced polyarthritis via central pain mechanisms, the analgesic effect of hypophysectomy was examined in the formalin test. The results show that hypophysectomy specifically prolongs the formalin interphase depression, further supporting that the underlying central pain suppression mechanisms are associated with resistance to adjuvant-induced polyarthritis.Corticotropin-releasing factor (CRF) was then investigated as a possible underlying mechanism of the effects of hypophysectomy. Peripheral injection of CRF into inflamed tissue affects pain mechanisms unrelated to the susceptibility to adjuvant-induced polyarthritis. However, central and intravenous administration of CRF preferentially affect the formalin interphase depression mechanisms. The observed dose-response relationships indicate that these effects are due to direct actions of CRF within the central nervous system.In conclusion, the results strongly suggest that the HPA axis modulates the susceptibility to adjuvant-induced polyarthritis via direct effects on supraspinal pain suppression mechanisms. Thus, the HPA axis may contribute to the development of chronic pain syndromes associated with HPA-axis abnormalities, such as rheumatoid arthritis and fibromyalgia, via effects on pain mechanisms within the central nervous system

Gene Therapy and Chronic Pain

Chronic, unremitting pain is perhaps the most common reason that patients seek medical care. In general, conservative techniques, such as medical management, are implemented as first-line therapy. Local anesthesia and lytic procedures, followed by interventional techniques, such as dorsal column stimulation and intrathecal drug delivery systems, are second-line therapies. However, for refractory and severe pain, which is not adequately controlled by other modes of therapy, new emerging options, including molecular or gene therapy, may become more widely utilized as experimental results are translated into clinical options

Genomic loci and candidate genes underlying inflammatory nociception

Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal acetic acid test, and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in 3 distinct groups of BXD RI mouse strains in 2 separate experiments. Combined mapping results detected 2 QTLs on chromosomes (Chr) 3 and 10 across experiments and groups of mice; an additional sex-specific QTL was detected on Chr 16. The results replicate previous findings of a significant QTL, Nociq2, on distal Chr 10 for formalin-induced inflammatory nociception and will aid in identification of the underlying candidate genes. Comparisons of sensitivity to intraperitoneal acetic acid in BXD RI mouse strains with microarray mRNA transcript expression profiles in specific brain areas detected covarying expression of candidate genes that are also found in the detected QTL confidence intervals. The results indicate that common and distinct genetic mechanisms underlie heritable sensitivity to diverse inflammatory insults, and provide a discrete set of high-priority candidate genes to investigate further in rodents and human association studies. Novel genomic regions linked to inflammatory nociception were detected, a previously reported locus was confirmed, and high-priority candidate genes for inflammatory nociception and pain were identified

for anonymous review

Laboratory conditions in biobehavioral experiments are commonly assumed to be `controlled', having little impact on the outcome. However, recent studies have illustrated that the laboratory environment has a robust effect on behavioral traits. Given that environmental factors can interact with trait-relevant genes, some have questioned the reliability and generalizability of behavior genetic research designed to identify those genes. This problem might be alleviated by the identification of the most relevant environmental factors, but the task is hindered by the large number of factors that typically vary between and within laboratories. We used a computational approach to retrospectively identify and rank sources of variability in nociceptive responses as they occurred in a typical research laboratory over several years. A machine-learning algorithm was applied to an archival data set of 8034 independent observations of baseline thermal nociceptive sensitivity. This analysis revealed that a factor even more important than mouse genotype was the experimenter performing the test, and that nociception can be affected by many additional laboratory factors including season/humidity, cage density, time of day, sex and within-cage order of testing. The results were confirmed by linear modeling in a subset of the data, and in confirmatory experiments, in which we were able to partition the variance of this complex trait among genetic (27%), environmental (42%) and genetic environmental (18%) sources. q 2003 Published by Elsevier Science Ltd