Sensation of abdominal pain induced by peritoneal carcinomatosis is accompanied by changes in the expression of substance P and μ-opioid receptors in the spinal cord of mice.
BACKGROUND
Patients with peritoneal carcinomatosis often report abdominal pain, which is relatively refractory to morphine. It has been considered that a new animal model is required to investigate the mechanism of abdominal pain for the development of optimal treatments for this type of pain.


METHODS
To prepare a peritoneal carcinomatosis model, highly peritoneal-seeding gastric cancer cells, 60As6, were implanted into the abdominal cavity. The nociceptive modality for pain-related behavior was assessed in terms of withdrawal behavior in response to mechanical stimuli and hunching behavior. Tissue samples from mouse dorsal root ganglia and spinal cord were subject to immunohistochemistry and real-time reverse transcription polymerase chain reaction.


RESULTS
Mice with peritoneal dissemination showed significant hypersensitivity of the abdomen to mechanical stimulation and spontaneous visceral pain-related behavior. There was a significant increase in c-Fos-positive cells in the spinal cord in tumor-bearing mice. Those mice exhibited a remarkable increase in substance P-positive neurons in the dorsal root ganglia (control vs. tumor, 15.4 ± 1.1 vs. 24.2 ± 3.6, P < 0.05, n = 3). A significant decreases in μ-opioid receptor expression mainly in substance P-positive neurons was observed in tumor-bearing mice (69.3 ± 4.9 vs. 38.7 ± 0.9, P < 0.05, n = 3), and a relatively higher dose of morphine was required to significantly reverse the abdominal hypersensitivity.


CONCLUSIONS
Both the up-regulation of substance P and down-regulation of μ-opioid receptor seen in the dorsal root ganglia may be, at least in part, responsible for the abdominal pain-like state associated with peritoneal carcinomatosis.
Division of Cancer Pathophysiology, Department of Palliative Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Masami
M
Suzuki
Minoru
M
Narita
Minami
M
Hasegawa
Sadayoshi
S
Furuta
Tomoyuki
T
Kawamata
Maho
M
Ashikawa
Kanako
K
Miyano
Kazuyoshi
K
Yanagihara
Fumiko
F
Chiwaki
Takahiro
T
Ochiya
Tsutomu
T
Suzuki
Motohiro
M
Matoba
Hiroki
H
Sasaki
Yasuhito
Y
Uezono
D015746:Abdominal Pain / Q000209:etiology* / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D001522:Behavior, Animal; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002277:Carcinoma / Q000150:complications* / Q000378:metabolism* / Q000523:psychology; D002460:Cell Line; D045744:Cell Line, Tumor; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000523:psychology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010195:Pancreatitis / Q000150:complications / Q000523:psychology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017450:Receptors, Opioid, mu / Q000096:biosynthesis* / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism*; D013373:Substance P / Q000096:biosynthesis* / Q000235:genetics
D016760:Proto-Oncogene Proteins c-fos; D017450:Receptors, Opioid, mu; D013373:Substance P; D008156:Luciferases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D015740:Calcitonin Gene-Related Peptide