Role of Spinal Cholecystokinin Octapeptide, Nociceptin/Orphanin FQ, and Hemokinin-1 in Diabetic Allodynia
Takafumi Hayashi,
Syu-ichi Kanno,
Chizuko Watanabe,
Damiana Scuteri,
Yasuyuki Agatsuma,
Akiyoshi Hara,
Giacinto Bagetta,
Tsukasa Sakurada,
Shinobu Sakurada
Affiliations
Takafumi Hayashi
Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
Syu-ichi Kanno
Division of Clinical Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
Chizuko Watanabe
Division of Physiology and Anatomy, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
Damiana Scuteri
Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
Yasuyuki Agatsuma
Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
Akiyoshi Hara
Division of Clinical Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
Giacinto Bagetta
Pharmacotechnology Documentation & Transfer Unit, Department of Pharmacy, Preclinical & Translational Pharmacology, Health & Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Tsukasa Sakurada
Faculty of Pharmacy, Daiichi University of Pharmacy, Fukuoka 815-8511, Japan
Shinobu Sakurada
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn.
