title: Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice.
abstract: Endothelin-1 (ET-1) exists in endothelial cells as well as a variety of other cell types. The presence of ET-1 and its receptors in neurons suggests its possible role as a neurotransmitter and/or neuromodulator. Studies utilizing exogenous ET-1 have suggested that ET-1 affects pain transmission. This study was designed to examine the possible role(s) of neuronal ET-1 in pain processing. We produced neuron-specific ET-1 knockout mice using the Cre/loxP system with a synapsin I promoter and examined the effects produced by the lack of neuronal ET-1 on pain behavior using common pain models and a model of stress-induced analgesia. In acute nociceptive pain models, paw withdrawal thresholds to radiant heat and mechanical stimuli applied with von Frey hairs were significantly lower in the knockout mice compared with control. This indicated that the absence of neuronal ET-1 leads to greater sensitivity to acute nociceptive stimuli. After inflammation was produced by intraplantar injection of carrageenan, there was a significantly greater degree of thermal hyperalgesia and mechanical allodynia in the knockout mice even after the difference in baseline values was compensated. Furthermore, in a neuropathic pain model produced by spinal nerve ligation, there was also a greater degree of mechanical allodynia in the knockout mice. Finally, in a swim-stress model, the magnitude of stress-induced analgesia was less in the knockout mice, indicating the involvement of neuronal ET-1 in stress-induced analgesia. The results suggest that there is a basal release of ET-1 from neurons that affect baseline pain thresholds as well as an additional release during persistent pain states that acts to suppress the pain. The involvement of neuronal ET-1 in stress-induced analgesia further suggests its role in endogenous pain inhibitory systems. To confirm that ET-1 is released in persistent pain states and to determine which part of the CNS is involved, we measured the concentrations of ET-1 before and after inducing peripheral inflammation in different parts of the CNS involved in endogenous pain inhibitory systems in normal mice. We found that ET-1 was increased in the hypothalamus while no significant increase was observed in the midbrain, medulla and spinal cord. The results of the present study suggest that neuronal ET-1 is involved in endogenous pain inhibitory control likely via pathways through the hypothalamus.
authors.affiliation: Department of Autonomic Physiology, 1-8-1, Nohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Hasue
authors.forename: T
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Y Y
authors.initials: YY
authors.lastname: Kisanuki
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: H
authors.initials: H
authors.lastname: Moriya
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuda
authors.forename: M
authors.initials: M
authors.lastname: Shimoyama
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000172:deficiency / Q000235:genetics*; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology; D009434:Neural Pathways / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D010148:Intractable Pain / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010812:Physical Stimulation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000503:physiopathology; D016704:Synapsins / Q000235:genetics
chemical_list: D019332:Endothelin-1; D016704:Synapsins