Original ArticlesThe peptide content of colonic afferents decreases following colonic inflammation
Introduction
Inflammation of somatic tissue due to injury produces sensitization of nociceptive primary afferents [52]. This peripheral sensitization is accompanied by an increase in neurotransmitter release, including the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), in both peripheral tissue and the spinal cord [9], [14], [36], [45], [48]. In the periphery these peptides contribute to the inflammatory process, further sensitizing primary afferent fibers (see [52] for review). In the spinal cord the increased afferent discharge increases the release of SP and CGRP [10], [11], [36], [45], which contribute to an increase in the excitability of dorsal horn neurons and ultimately to hyperalgesia [29], [43], [51], [53].
Similar to somatic tissue, inflammation of visceral tissue leads to sensitization of visceral afferents [3], [17], [18], [19], [47] and increased pain states [2], [39]. Neuropeptides are found in the majority of visceral afferents (see [7] for review) and these neuropeptides contribute to the production of pain at several levels. In the periphery, SP acting at NK-1 receptors evokes plasma extravasation from the gastrointestinal tract [13]. This can be evoked by acute capsaicin [13] and blocked by capsaicin pretreatment [41], supporting a role for SP in neurogenic inflammation of visceral tissue. Further, continuous systemic infusion of an NK-1 receptor antagonist blocks sensitization of pelvic nerve afferents by chronic inflammation of the colon (V. Julia and G.F. Gebhart, unpublished observations), suggesting that, similar to somatic tissue, a consequence of SP in the inflammatory process is sensitization of visceral afferents. CGRP is also localized to visceral afferents [4], [7], [49], [54], but its contribution to visceral pain is unclear. CGRP appears to have a protective effect in peripheral tissue by reducing ulcerative lesions during inflammation [12]. However, the CGRP receptor antagonist hCGRP8–37 attenuated abdominal contractions (a measure of visceral pain) following colorectal distention or intraperitoneal (IP) injection of acetic acid [24], [42].
The role of neuropeptides in mediating spinal mechanisms of visceral pain is less well studied although preliminary evidence suggests a role for neuropeptides in visceral pain processing. In the spinal cord dorsal horn, SP contributes to the generation of central sensitization; NK-1 receptor antagonists attenuate sensitization of dorsal horn neurons following repetitive noxious colorectal distention (R.J. Traub, unpublished observations), suggesting a role in visceral hyperalgesia. Likewise, intrathecal administration of a CGRP receptor antagonist attenuated the visceromotor reflex in rats with colonic inflammation [42].
Given the similarity of central and peripheral function of neuropeptides identified in both somatic and visceral afferents, we hypothesized that changes observed in visceral afferents as a result of colonic inflammation would mirror similar changes reported in somatic afferents following peripheral inflammation. We report here changes in the content of SP and CGRP, following colonic inflammation, consistent with a putative role of these peptides in spinal mechanisms of visceral pain.
Section snippets
Methods
All procedures were approved by the University of Iowa Animal Care and Use Committee and conform to the guidelines for the ethical treatment of animals by the International Association for the Study of Pain.
Male Sprague–Dawley rats (300–390 g; Harlan, Indianapolis, IN; n = 22) were anesthetized with Nembutal (50 mg/kg) and the descending colon and rectum were exposed through a midline abdominal incision. Approximately 30 μl Fluorogold (FG; 4% in saline) was injected subserosally into the
Results
The cell bodies of primary afferents that innervate the descending colon were labeled by injection of FG into the colon. After a 7–10 day survival period, FG-labeled cells were observed in the T13-L2 and L6-S2 DRG (Fig. 1 ). Injections labeled DRG cells bilaterally and no difference in the number of labeled ganglion cells between sides was seen so data from both sides were pooled. Further, the T13-L2 ganglia and the L6-S2 ganglia from each animal were grouped together prior to tissue
Discussion
This study examined the effects of colonic inflammation on the content of SP and CGRP in DRG cell bodies of colonic afferents and documented the colocalization of Som in colonic afferents. In noninflamed control rats, 60–70% of the colonic afferents labeled immunocytochemically for SP or CGRP. This is similar to data previously reported for colonic afferents [26], and consistent with studies showing that gastric [16] and ureter [46] spinal afferents are rich in these peptides. Interestingly, we
Acknowledgments
Supported by NS 19112 and NS 30604.
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