Tumor-evoked sensitization of C nociceptors: a role for endothelin.
Primary and metastatic cancers that effect bone are frequently associated with pain. Sensitization of primary afferent C nociceptors innervating tissue near the tumor likely contributes to the chronic pain and hyperalgesia accompanying this condition. This study focused on the role of the endogenous peptide endothelin-1 (ET-1) as a potential peripheral algogen implicated in the process of cancer pain. Electrophysiological response properties, including ongoing activity and responses evoked by heat stimuli, of C nociceptors were recorded in vivo from the tibial nerve in anesthetized control mice and mice exhibiting mechanical hyperalgesia following implantation of fibrosarcoma cells into and around the calcaneus bone. ET-1 (100 microM) injected into the receptive fields of C nociceptors innervating the plantar surface of the hind paw evoked an increase in ongoing activity in both control and tumor-bearing mice. Moreover, the selective ETA receptor antagonist, BQ-123 (3 mM), attenuated tumor-evoked ongoing activity in tumor-bearing mice. Whereas ET-1 produced sensitization of C nociceptors to heat stimuli in control mice, C nociceptors in tumor-bearing mice were sensitized to heat, and their responses were not further increased by ET-1. Importantly, administration of BQ-123 attenuated tumor-evoked sensitization of C nociceptors to heat. We conclude that ET-1 at the tumor site contributes to tumor-evoked excitation and sensitization of C nociceptors through an ETA receptor mediated mechanism.
Hamamoto
Darryl T
DT
Department of Diagnostic and Biological Sciences, University of Minnesota, 515 Delaware St. SE, 17-252 Moos Tower, Minneapolis, MN 55455, USA.
Khasabov
Sergey G
SG
Cain
David M
DM
Simone
Donald A
DA
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D045744:Cell Line, Tumor; D004594:Electrophysiology; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins / Q000378:metabolism / Q000502:physiology*; D005354:Fibrosarcoma / Q000473:pathology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000150:complications* / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D009431:Neural Conduction / Q000502:physiology; D009475:Neurons, Afferent / Q000378:metabolism / Q000502:physiology; D009619:Nociceptors / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology / Q000523:psychology
D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)