title: Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin.
abstract: Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.
authors.affiliation: Institute of Neuroscience, Biomedical Research Center, University of Granada, 18100 Armilla, Granada, Spain.|Animal Behavior Research Unit, Scientific Instrumentation Center, University of Granada, 18100 Armilla, Granada, Spain.|Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Entrena
authors.affiliation: Institute of Neuroscience, Biomedical Research Center, University of Granada, 18100 Armilla, Granada, Spain.|Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain.|Department of Pharmacology, School of Medicine, University of Granada, 18016 Granada, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Sánchez-Fernández
authors.affiliation: Institute of Neuroscience, Biomedical Research Center, University of Granada, 18100 Armilla, Granada, Spain.|Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain.|Department of Pharmacology, School of Medicine, University of Granada, 18016 Granada, Spain.
authors.forename: F R
authors.initials: FR
authors.lastname: Nieto
authors.affiliation: Institute of Neuroscience, Biomedical Research Center, University of Granada, 18100 Armilla, Granada, Spain.|Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain.|Department of Pharmacology, School of Medicine, University of Granada, 18016 Granada, Spain.
authors.forename: R
authors.initials: R
authors.lastname: González-Cano
authors.affiliation: Drug Discovery and Preclinical Development, Esteve, 08041, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Yeste
authors.affiliation: Institute of Neuroscience, Biomedical Research Center, University of Granada, 18100 Armilla, Granada, Spain.|Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain.|Department of Pharmacology, School of Medicine, University of Granada, 18016 Granada, Spain.|Teófilo Hernando Institute for Drug Discovery, 28029 Madrid, Spain.
authors.forename: E J
authors.initials: EJ
authors.lastname: Cobos
authors.affiliation: Institute of Neuroscience, Biomedical Research Center, University of Granada, 18100 Armilla, Granada, Spain.|Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain.|Department of Pharmacology, School of Medicine, University of Granada, 18016 Granada, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Baeyens
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000009:adverse effects; D003517:Cyclopentanes / Q000009:adverse effects*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009025:Morpholines / Q000009:adverse effects*; D059225:Nociception; D010147:Pain Measurement; D017288:Pain Threshold; D010423:Pentazocine / Q000009:adverse effects*; D017480:Receptors, sigma / Q000819:agonists*; D000097605:Sigma-1 Receptor
chemical_list: D002211:Capsaicin; D003517:Cyclopentanes; D009025:Morpholines; D010423:Pentazocine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C018861:carbetapentane