Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice.
We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(1)-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [(3)H](+)-pentazocine binding assays. Both wild-type and sigma(1)-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.05-8 g force), ranging from innocuous to noxious, applied to the hind paw. This indicates that sigma(1) gene inactivation does not modify the perception of punctate mechanical stimuli. The intraplantar (i.pl.) administration of capsaicin induced dose-dependent mechanical allodynia in wild-type mice (markedly reducing both the threshold force necessary to induce paw withdrawal and the latency to paw withdrawal induced by a given force). In contrast, capsaicin was completely unable to induce mechanical hypersensitivity in sigma(1)-KO mice. The high-affinity and selective sigma(1) antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 microg,i.pl.), yielding ED(50) (mg/kg) values of 15.80+/-0.93, 29.31+/-1.65 and 40.74+/-7.20, respectively. The effects of the sigma(1) antagonists were reversed by the sigma(1) agonist PRE-084 (32 mg/kg, s.c.). None of the drugs tested modified the responses induced by a painful mechanical punctate stimulus (4 g force) in nonsensitized animals. These results suggest that sigma(1) receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.
Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, University of Granada, Avenida de Madrid 11, 18012 Granada, Spain Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, Armilla, 18100 Granada, Spain Laboratorios Dr. Esteve S.A., Avenida Virgen de Montserrat 221, 08041 Barcelona, Spain.
José Manuel
JM
Entrena
Enrique José
EJ
Cobos
Francisco Rafael
FR
Nieto
Cruz Miguel
CM
Cendán
Georgia
G
Gris
Esperanza
E
Del Pozo
Daniel
D
Zamanillo
José Manuel
JM
Baeyens
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010812:Physical Stimulation; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011437:Propylamines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D018689:Sensory System Agents / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D000840:Anisoles; D002211:Capsaicin; D004247:DNA; D005029:Ethylenediamines; D009025:Morpholines; D010879:Piperazines; D011437:Propylamines; D017480:Receptors, sigma; D018689:Sensory System Agents; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin