Possible chemical contribution from chromic gut sutures produces disorders of pain sensation like those seen in man

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Abstract
Recently, it has been reported that loosely constrictive chromic gut ligatures around the sciatic nerve produce behavioral evidence of neuropathic pain in rats. It has been shown that axonal swelling after ligation results in a constriction injury associated with a decrease in the number of both large-diameter myelinated and small-diameter unmyelinated axons, but the mechanism(s) producing spontaneous pain and thermal hyperalgesia remain largely unknown. The present study systematically evaluated potential mechanisms involved in development of the behavioral changes produced by chromic gut ligatures loosely tied around the sciatic nerve. Four ligatures of either silk (4-0), plain gut (4-0), or chromic gut (4-0, 3-0, or 2-0) were placed loosely around the left sciatic nerve of male Sprague-Dawley rats. An additional group of rats had 8 × 0.5 cm sections of 4-0 chromic gut laid adjacent to the left sciatic nerve. The right sciatic nerve was exposed in all rats for sham surgery. The posture and gait of all rats was qualitatively assessed before (day 0) and for 20–30 days after surgery. Rats were tested for evidence of thermal and mechanical hyperalgesia prior to surgery, and on postoperative days 3, 5, 10, 20 and, in some groups, on day 30. Chromic gut, but not plain gut or silk, ligatures placed around or laid next to the sciatic nerve produced an alteration in the posture of rats such that most of the pressure was placed on the heel and medial aspect of the left (ligated) hind paw with the toes held together and plantar-flexed while pressure appeared to be evenly distributed on the right (sham) hind paw. As a result, a pronounced limp was evident, often with the left hind paw held in the air for prolonged periods of time during the first few days after surgery. These postural changes were most pronounced in the 2-0 and 3-0 chromic gut-treated rats. Chromic gut sutures (4-0, 3-0, or 2-0) tied loosely around the left sciatic nerve also produced a ‘dose-dependent’ decrease in thermal withdrawal latency that was maximal on postoperative day 3 (25%, 39%, and 41%, respectively). The magnitude of the thermal hyperalgesia declined over time such that a return to baseline was observed by postoperative day 20 in 4-0 and 3-0 chromic gut-treated rats. 4-0 chromic gut laid adjacent to the sciatic nerve also produced a decrease in thermal withdrawal latency of 22% that was maximal on postoperative day 5 and returned to baseline by day 10. In contrast, neither 4-0 silk nor 4-0 plain gut produced any evidence of thermal hyperalgesia. There was no evidence of mechanical hyperalgesia on any day tested in rats from any of the 6 groups. Light microscopic examination of Toluidine Blue-stained sections of the sciatic nerve through the ligature site revealed that there was no evidence of a significant change in content of large- or small-diameter myelinated axons compared to the right (sham) sciatic nerve in silk, plain gut, or 4-0 chromic gut-treated rats. Examination of sciatic nerves from rats treated with 3-0 or 2-0 chromic gut showed variable changes in the numbers of large- and small-diameter myelinated axons compared to the right (sham) sciatic nerve in the same rats. These data support the hypothesis that a chemical component of chromic gut sutures interacts with sciatic/sympathetic nerves to produce behavioral evidence of neuropathic pain and that a constriction injury may not be a necessary requirement for development of the thermal hyperalgesia and the guarding behavior produced by loose chromic gut ligation of the sciatic nerve.