Richard J. Traub

Colonic inflammation induces fos expression in the thoracolumbar spinal cord increasing activity in the spinoparabrachial pathway.

&NA; The descending colon and rectum are innervated by primary afferent fibers projecting to the lumbosacral and thoracolumbar spinal cord segments. Previous work from this laboratory has suggested that afferent input and sensory processing in the lumbosacral spinal cord is necessary and sufficient to mediate reflex responses to transient colorectal stimulation while processing in both the lumbosacral and thoracolumbar spinal cord segments contribute to visceral hyperalgesia. In the rat, repetitive noxious colorectal distention (CRD) induces >200 Fos labeled cells per section in the lumbosacral segments, but few in the thoracolumbar segments, further suggesting that transient colonic nociceptive input is transduced primarily in the lumbosacral spinal cord. The laminar distribution of this CRD‐induced Fos suggests some of these neurons project to the parabrachial nucleus (PBn), an important relay for visceroceptive input from the spinal cord to higher order centers for nociceptive processing. In this study, two hypotheses were tested: first, inflammation of the colon prior to CRD would induce Fos expression in neurons in the thoracolumbar spinal cord segments and increase the number of neurons in the lumbosacral spinal cord segments that express Fos in response to noxious CRD; and second, the inflammation‐induced increase in Fos expression in the spinal cord would be partially manifest as an increase in the number of spinoparabrachial projection neurons that respond to CRD. The retrograde tracer Fluorogold (FG) was injected unilaterally into the PBn of male Sprague–Dawley rats. Ten to 14 days later the rats colon was either distended or inflamed and distended. Sections from the T13‐L2 and L6‐S2 spinal cord segments were double labeled using antibodies directed against FG and Fos protein. The results show that: (1) colonic inflammation plus distention induced Fos expression in the thoracolumbar spinal cord and increased Fos expression in the lumbosacral spinal cord compared to distention alone. In the lumbosacral cord, the increase in Fos expression was localized primarily to the superficial dorsal horn (SDH). In the thoracolumbar spinal segments, Fos was induced primarily in the SDH and the area around the central canal. (2) Injection of FG into the PBn produced dense retrograde labeling in the SDH, the lateral deeper gray matter and the area around the central canal at the lumbosacral and thoracolumbar levels. (3) In the lumbosacral spinal cord, 30–40% of the FG labeled cells double labeled for Fos. Colonic inflammation plus CRD did not significantly increase the percentage of spinoparabrachial neurons that were labeled for Fos compared to distention alone. (4) In the thoracolumbar spinal cord less than 10% of the FG labeled neurons were double labeled for Fos following CRD, but 25% of the FG labeled neurons in the SDH were double labeled following colonic inflammation. These data support the hypothesis that colonic inflammation activates viscerosensory processing in the thoracolumbar spinal cord and further suggests that this information is relayed to the PBn. The increase in information reaching the PBn over these parallel pathways may contribute to the affective‐motivational component of the pain experience.

Colonic inflammation decreases thermal sensitivity of the forepaw and hindpaw in the rat

Noxious stimulation at one site on the body can inhibit noxious stimulation at distal body sites. This has been extensively demonstrated for somatic stimuli, but less so for visceral stimuli. In the present study we present a model for visceral inflammatory stimuli inhibiting somatic thermal sensitivity in awake rats. Colonic inflammation induced by mustard oil increases the hindpaw and forepaw withdrawal latency from a noxious radiant heat source by 35-50% compared to baseline responses. The duration of the effect is dose-dependent. The withdrawal latency in control rats (mineral oil in colon, mustard oil on skin) was not affected. Rotarod performance was not affected by 5% mustard oil indicating that colonic inflammation did not produce a general malaise or decrease in motor performance. These data suggest that visceral inflammation in the rat decreases somatic sensitivity similar to that reported by patients with colonic hypersensitivity from irritable bowel syndrome or inflammatory bowel diseases.

Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats

Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stress-induced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome.

Opposing Roles of Estradiol and Testosterone on Stress-Induced Visceral Hypersensitivity in Rats

Chronic stress produces maladaptive pain responses, manifested as alterations in pain processing and exacerbation of chronic pain conditions including irritable bowel syndrome. Female predominance, especially during reproductive years, strongly suggests a role of gonadal hormones. However, gonadal hormone modulation of stress-induced pain hypersensitivity is not well understood. In the present study, we tested the hypothesis that estradiol is pronociceptive and testosterone is antinociceptive in a model of stress-induced visceral hypersensitivity (SIVH) in rats by recording the visceromotor response to colorectal distention after a 3-day forced swim (FS) stress paradigm. FS induced visceral hypersensitivity that persisted at least 2 weeks in female, but only 2 days in male rats. Ovariectomy blocked and orchiectomy facilitated SIVH. Furthermore, estradiol injection in intact male rats increased SIVH and testosterone in intact female rats attenuated SIVH. Western blot analyses indicated estradiol increased excitatory glutamate ionotropic receptor NMDA type subunit 1 expression and decreased inhibitory metabotropic glutamate receptor 2 expression after FS in male thoracolumbar spinal cord. In addition, the presence of estradiol during stress increased spinal brain-derived neurotrophic factor (BDNF) expression independent of sex. In contrast, testosterone blocked the stress-induced increase in BDNF expression in female rats. These data suggest that estradiol facilitates and testosterone attenuates SIVH by modulating spinal excitatory and inhibitory glutamatergic receptor expression. PERSPECTIVE SIVH is more robust in female rats. Estradiol facilitates whereas testosterone dampens the development of SIVH. This could partially explain the greater prevalence of certain chronic visceral pain conditions in women. An increase in spinal BDNF is concomitant with increased stress-induced pain. Pharmaceutical interventions targeting this molecule could provide promising alleviation of SIVH in women.

Do MicroRNAs Modulate Visceral Pain

Visceral pain, a common characteristic of multiple diseases relative to viscera, impacts millions of people worldwide. Although hundreds of studies have explored mechanisms underlying visceral pain, it is still poorly managed. Over the past decade, strong evidence emerged suggesting that microRNAs (miRNAs) play a significant role in visceral nociception through altering neurotransmitters, receptors and other genes at the posttranscriptional level. Under pathological conditions, one kind of miRNA may have several target mRNAs and several kinds of miRNAs may act on one target, suggesting complex interactions and mechanisms between miRNAs and target genes lead to pathological states. In this review we report on recent progress in examining miRNAs responsible for visceral sensitization and provide miRNA-based therapeutic targets for the management of visceral pain.

Onderzoek naar sekse- en genderspecifieke verschillen bij pijn en analgesie: een consensusverslag 1

In september 2006 kwamen de leden van de belangengroepering (SIG) sekse- en genderspecifieke pijn van de International Association for the Study of Pain (IASP, de internationele associatie voor pijnonderzoek) bijeen om over de volgende onderwerpen te discussieren: 1) Wat is er bekend over sekse- en genderverschillen op het gebied van pijn en analgesie; en 2) Wat zijn de ‘best practice’-richtlijnen voor sekse- en genderspecifiek pijnonderzoek? Dit verslag is de consensus van deze bijeenkomst en omvat bijdragen uit algemeen wetenschappelijke hoek, van onderzoekers op het gebied van klinische en psychosociale pijn en van erkende deskundigen op het gebied van seksuele differentiatie en reproductieve endocrinologie.