Recent advances in chronic visceral pain

The Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Whitechapel, London, UK.
Current opinion in supportive and palliative care (Impact Factor: 1.66). 07/2008; 2(2):116-21. DOI: 10.1097/SPC.0b013e328300548a
Source: PubMed

ABSTRACT Chronic visceral pain is one of the most common causes of morbidity in the general population. Despite a gargantuan effort from academia and the pharmaceutical industry, an integrated understanding of the pathophysiological mechanisms of chronic visceral pain, particularly with respect to functional gastrointestinal disorders, remains incomplete.
Advances in our understanding of the structure and function of the microanatomy of nociception has led to the identification of a number of ion channels, neurotransmitter receptors and trophic factors that may be intimately involved in chronic visceral pain. These advances have been paralleled with those in the fields of genetics, neurophysiology and functional neuroimaging. These advances have allowed the objective assessment of central processing of visceral sensation and furthermore the factors that may modulate this process in health and disease.
These findings have important implications for the future direction of research. The real challenge for the future progress is to further characterize patients with chronic visceral pain in terms of their clinical phenotype, genotyping and nociceptive physiology on an individual basis towards the development of more efficacious therapeutic strategies.

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    • "These pain categories are the most refractory to effective treatment, in part due to its diverse nature and the contribution of distinct and redundant mechanisms that are incompletely understood and differ from the better studied somatic nociceptive system [2]. Inflammation plays a significant role in the peripheral and central sensitization seen in a subgroup of subjects [3]. "
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    ABSTRACT: Visceral pain is the most common reason for physician visits in US. Glutamate is the major excitatory neurotransmitter and mediates visceral nociceptive neuro-transmission and hypersensitivity. Removal of extracellular glutamate is predominantly mediated by glial glutamate transporter-1 (GLT-1). The pharmacological approach to up-regulate GLT-1 by 1 week administration of ceftriaxone (CTX) has been successful to mitigate visceral nociception. The present study shows that intrathecal delivery of selective GLT-1 antagonist dihydrokainate reversed CTX-blunted visceral nociceptive response, suggesting a spinal site of action. The role of GLT-1 up-regulation in animal models of colitis was studied. CTX treatment reversed TNBS-induced visceral hypersensitivity. In addition, CTX treatment initiated one week after the onset of DSS-induced visceral inflammation also attenuated visceral hypersensitivity, revealing a potential therapeutic effect. Cephalothin, a cephalosporin antibiotic lacking GLT-1 induction activity, failed to attenuate visceral nociception. CTX-induced changes in fecal microbiota do not support a role of probiotic effects in mitigating visceral nociception/hypersensitivity. Finally, adeno-associated virus serotype 9-mediated GLT-1 over-expression was effective to mitigate visceromotor response to 60 mmHg colo-rectal distension. These studies indicate that GLT-1 over-expression is a novel and effective method to attenuate visceral nociception, and is deserving of further study as a translationally relevant approach to treat visceral pain.
    Pain Research and Treatment 12/2011; 2011(2-3):507029. DOI:10.1155/2011/507029
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    ABSTRACT: Most forms of visceral pain generate intense referred hyperalgesia but the mechanisms of this enhanced visceral hypersensitivity are not known. The on-cells of the rostral ventromedial medulla (RVM) play an important role in descending nociceptive facilitation and can be sensitized to somatic mechanical stimulation following peripheral nerve injury or hindpaw inflammation. Here we have tested the hypothesis that visceral noxious stimulation sensitizes RVM ON-like cells, thus promoting an enhanced descending facilitation that can lead to referred visceral hyperalgesia. Intracolonic capsaicin instillation (ICI) was applied to rats in order to create a hyperalgesic state dependent on noxious visceral stimulation. This instillation produced acute pain-related behaviors and prolonged referred hyperalgesia that were prevented by the RVM microinjection of AP5, an NMDA selective antagonist. In electrophysiological experiments, ON-like RVM neurons showed ongoing spontaneous activity following ICI that lasted for approximately 20 min and an enhanced responsiveness to von Frey and heat stimulation of the hindpaw and to colorectal distention (CRD) that lasted for at least 50 min post capsaicin administration. Moreover, ON-like cells acquired a novel response to CRD and responded to heat stimulation in the innocuous range. OFF-like neurons responded to capsaicin administration with a brief (<5 min) inhibition of activity followed by an enhanced inhibition to noxious stimulation and a novel inhibition to innocuous stimulation (CRD and heat) at early time points (10 min post capsaicin). These results support the hypothesis that noxious visceral stimulation may cause referred hypersensitivity by promoting long-lasting sensitization of RVM ON-like cells.
    European journal of pain (London, England) 06/2009; 14(2):120.e1-9. DOI:10.1016/j.ejpain.2009.04.006 · 2.93 Impact Factor
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    ABSTRACT: Visceral pain is a significant issue for patients, and the importance of treating pain is underestimated. New opioid formulations, the primary treatment option for moderate-to-severe pain, have been shown to be effective, but no studies have been conducted to address the efficacy of these agents for visceral pain. This study was conducted to determine the incidence of visceral pain in patients with uncontrolled moderate-to-severe pain, and to evaluate the efficacy of controlled-release (CR) oxycodone in this context. s: In this multicenter, prospective, observational study, 967 of 980 evaluated patients were included, 350 (36.2%) of whom presented mainly visceral pain. In most cases (57.0%), patients had experienced pain for < or = 3 months, and the majority (94.9%) were cancer patients. Pain was uncontrolled in 340 (97.1%) patients, and was rated as severe in >2/3 of patients (mean numerical rating scale (NRS) value 7.04 +/- 1.68). Patients with uncontrolled pain were given oxycodone CR; all completed the 15-day study and no patient was switched to an alternative opioid. Oxycodone CR was associated with significant reductions in mean NRS value at day 3, 7 and 15 (final mean NRS 2.37 +/- 1.59) and the proportion of patients experiencing severe pain had decreased by the end of the study to 1.5%. The SF-12 questionnaire showed significant improvements in quality of life in all domains, and oxycodone CR was well tolerated. Oxycodone CR appears to be a very well tolerated and effective treatment for patients with visceral pain.
    European review for medical and pharmacological sciences 03/2010; 14(3):185-90. · 1.21 Impact Factor
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