Activation of nociceptive neurons in T9 and T10 in cerulein pancreatitis

Abstract

Mechanisms of pain transduction in acute pancreatitis are poorly understood. Increased Fos expression in the spinal cord is a marker of activation of nociceptive neurons. We hypothesized that cerulein pancreatitis leads to increased Fos expression at T9 and T10, which receive sensory input from the pancreas. Rats were injected with cerulein (100 μg/kg, s.c.) or saline carrier (NS). Endpoints at 4, 6, and 10 h were serum amylase, myeloperoxidase activity (MPO), and spinal cord Fos expression (number of immunoreactive nuclei/section dorsal gray matter). Fos-like immunoreactivity (FLI) at T9-T10 was compared to internal controls (T6, T12). An average of 20 spinal cord histologic sections were evaluated per rat. Some animals were injected with the μ-opioid receptor agonist, buprenorphine (90 μg/kg, s.c.), 3 h after cerulein, and their endpoints were measured at 6 h. Analysis of variance and t tests were used for statistical analysis. Results are means ± SEM. As expected, cerulein induced edematous pancreatitis, with a 4-fold increase in serum amylase at 6 h [cer ( n = 8): 14,000 ± 1,300 U/ml versus NS ( n = 10): 3,700 ± 300, P < 0.005)] and a 2-fold increase in MPO activity (0.25 ± 0.05) activity units/dry wt versus 0.13 ± 0.02, P < 0.05). Cerulein induced nearly a 2-fold increase in FLI at T9 and T10 [ n = 10 (cer) and n = 13 (NS): T9, 14 ± 1.5 versus 7.8 ± 0.88; T10, 15 ± 1.7 versus 8.3 ± 0.70; P < 0.05]. Peak effects of cerulein on FLI occurred at 6 h and were greatest at T9/T10 with relative sparing of T6/T12. T6/T12 expression was similar in experimental and control groups. Buprenorphine significantly reduced both serum amylase and FLI and T9/T10. Cerulein-induced acute pancreatitis in rat increases visceral nociceptive signaling at spinal cord levels T9 and T10, with a peak at 6 h. Blockade of this effect by the μ-opioid receptor agonist buprenorphine could occur either by direct activation of central opioid receptors and/or an anti-inflammatory mechanism. FLI is a useful tool for studying the pathophysiology of pain in experimental acute pancreatitis.