Spinal cord stimulation attenuates visceromotor reflexes in a rat model of post-inflammatory colonic hypersensitivity
Introduction
Chronic visceral pain of gastrointestinal origin is poorly understood and lacks an effective therapy. Abdominal pain and discomfort is the major complaint in patients with irritable bowel syndrome (IBS). Abnormal (or heightened) visceral sensory perception has been proposed to account for many of the symptoms of IBS. Evidence in support of this concept consists of the observation that gastrointestinal distention in patients with IBS evokes pain at lower distention pressures compared to asymptomatic control subjects (Ritchie, 1973, Whitehead et al., 1990, Lembo et al., 1996). Interestingly, significant subsets of patients that recover from an acute infectious gastroenteritis also exhibit IBS symptomatology (Chaudhary and Truelove, 1962, Bergin et al., 1993, Collins et al., 1999). Moreover, in patients with inflammatory bowel disease (IBD), remission and recovery from gastrointestinal inflammation is associated with IBS-like symptoms (Isgar et al., 1983).
A model for quantifying the level of visceral sensation in rats by measuring visceromotor behavioral responses (VMR) induced by colorectal distention has been developed (Ness and Gebhart, 1988). This model has been modified by using trinitrobenzenesulfonic acid to produce a post-inflammatory visceral hypersensitivity in rats. This hypersensitivity resembles that observed in patients with IBS who have recovered from an acute colonic inflammation (Gibson and Greenwood-Van Meerveld, 2000). Studies have shown that in response to sensitization, innocuous colorectal distention evokes a VMR, which resembles that induced by nociceptive stimuli in non-sensitized rats (Greenwood-Van Meerveld et al., 2002). These findings strongly suggest that alterations in neuronal activity within the spinal cord may be involved in processing information from the colon, and that induced abnormalities in spinal neuronal processing may lead to the development of visceral hypersensitivity.
Electrical stimulation of the dorsal columns of the spinal cord (spinal cord stimulation; SCS) has been employed for more than 30 years to treat chronic severe pain (Meyerson and Linderoth, 2000). The cardinal indication for using this treatment is neuropathic pain, which is often due to nerve root or peripheral nerve lesions; but also, nociceptive pain, as seen for example in an ischemic limb, has responded well to SCS (Meyerson and Linderoth, 2000, Linderoth et al., 2005). The mechanism by which SCS provides pain relief is poorly understood but may involve both spinal and supraspinal neural circuits (Linderoth and Foreman, 1999, Linderoth and Meyerson, 2002). The mechanisms of pain relief for neurogenic and ischemic pain by SCS are probably fundamentally different for neurogenic and ischemic pain (Linderoth and Foreman, 1999). In neurogenic pain the pain-perpetuating neural mechanisms seem to be counteracted more directly (Linderoth and Meyerson, 2002) while in ischemic pain the effects of SCS on tissue ischemia itself are considered to be the phenomenon leading to a secondary relief of the pain. Since SCS has been demonstrated in animal models of neuropathic pain, to suppress neuronal hyperexcitability in the spinal cord (Yakhnitsa et al., 1999), it might be possible that similar effects could be exerted on pathological neuronal processing induced by colorectal distension of a hypersensitive colon. Additional effects on ischemic pain, complex regional pain syndromes and on elevated viscerosomatic reflex activity may be obtained by the effects of SCS on sympathetic activity (Linderoth et al., 1994, Linderoth and Foreman, 1999, Tanaka et al., 2003) or via recently demonstrated antidromic mechanisms (Croom et al., 1998, Linderoth and Foreman, 1999, Tanaka et al., 2003).
The purpose of the present study was to determine if SCS affected viscerosomatic reflexes in animals with a hypersensitive colon. Effects of SCS on visceral functions have earlier been reported, e.g. effects on bladder hypersensitivity in MS cases (Tallis et al., 1983) and single reports on intestinal function (Kemler et al., 2001). In an earlier animal study that examined the effects of SCS on enhanced viscerosomatic reflexes in a model of acute colonic hypersensitivity, we observed a potent inhibitory effect of SCS on abdominal spasms resulting from colorectal distensions (Greenwood-Van Meerveld et al., 2003). Based on this report, one single patient with IBS was implanted with a SCS system (Krames and Mousad, 2004). The effect on episodes of diarrhea, pain, etc. was remarkable. Since few effective therapies exist for IBS, this case study induced hope for a new therapeutic strategy. However, the scientific basis for a larger human study is still weak and the first animal study was performed using a model of acute colonic hypersensitivity. Therefore, in the current study we examined whether SCS can modulate viscerosomatic reflexes in a rodent model of the post-inflammatory colonic hypersensitivity performed at a stage where the colonic histology should again appear normal. It is important to note that compared to rat models in which colonic hypersensitivity is observed during active colitis (Ness and Gebhart, 2001), it is our model of post-inflammatory colonic hypersensitivity which more closely mimics the pathophysiological conditions observed in patients with post-infective IBS.
Section snippets
Animals
Experiments were performed on male Sprague Dawley rats (Charles Rivers, Wilmington, MA), housed under controlled conditions (21 °C, 0600–1800 hours light/dark cycle) with availability to standard rat chow and water ad libitum. Upon arrival, each rat was double-housed for 7 days and acclimated to the animal facility. To reduce the stress associated with experimentation, each rat underwent a second 7-day period of habituation to the experimental environment. During this acclimatization period,
Results
Compared to saline-enema treated control rats, within 3 days of the TNBS (50 mg/kg in 50% ethanol) enema, there was an active colonic inflammatory response as demonstrated by an increase in the colonic damage score and elevated levels of myeloperoxidase activity derived from inflammatory cells (Table 1). During the phase of active colitis the rats experienced soft stool/diarrhea and lost weight (approx. 5%). However, 30 days after the TNBS enema there was a complete recovery from the colitis.
Discussion
The present study in a rat model of post-inflammatory colonic hypersensitivity showed that SCS suppressed the viscerosomatic responses to low levels of colorectal distension after recovery from the inflammation (day 30 post-TNBS) but did not affect the reflexes during the active phase of colonic inflammation (day 3). This study extended the observations made in a previous study that SCS strongly suppressed abdominal reflex contractions induced by nociceptive levels of colorectal distension in
Acknowledgements
The authors would like to thank the Presbyterian Health Foundation for their support of this research project. The technical assistance of Sofia Siswanto and Gote Hammarstrom (KI) are very much appreciated.
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