Intrathecal administration of sigma-1 receptor agonists facilitates nociception: involvement of a protein kinase C-dependent pathway.
Sigma sites, originally proposed as opioid receptor subtypes, are currently thought to represent unique receptors with a specific pattern of drug selectivity, a well-established anatomical distribution and broad range of functional roles including potential involvement in nociceptive mechanisms. We have recently demonstrated that intrathecal (i.t.) treatment with a sigma-1 receptor antagonist reduced formalin-induced pain behavior. In the present study, we investigated the potential role of spinal sigma-1 receptor agonists in peripherally initiated nociception and attempted to elucidate intracellular signaling mechanisms associated with spinal cord sigma-1 receptor activation in mice. The i.t. injection of the sigma-1 receptor agonists PRE-084 (PRE) or carbetapentane (CAR) significantly decreased tail-flick latency (TFL) and increased the frequency of paw withdrawal responses to mechanical stimulation (von Frey filament, 0.6 g) as well as the amount of Fos expression in the spinal cord dorsal horn induced by noxious paw-pinch stimulation. These PRE- or CAR-induced facilitatory effects on nociception were significantly blocked by i.t. pretreatment with the sigma-1 receptor antagonist, BD-1047, the phospholipase C (PLC) inhibitor, U-73,122, the Ca(2+)-ATPase inhibitor, thapsigargin, and the protein kinase C (PKC) inhibitor, chelerythrine. Western blot analysis further revealed that i.t. PRE or CAR injection significantly increased pan-PKC as well as the PKCalpha, epsilon, and zeta isoforms in the dorsal horn. Collectively, these findings demonstrate that calcium-dependent second messenger cascades including PKC are involved in the facilitation of nociception associated with spinal sigma-1 receptor activation.
Roh
Dae-Hyun
DH
Department of Veterinary Physiology, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, South Korea.
Kim
Hyun-Woo
HW
Yoon
Seo-Yeon
SY
Seo
Hyoung-Sig
HS
Kwon
Young-Bae
YB
Kim
Kee-Won
KW
Han
Ho-Jae
HJ
Beitz
Alvin J
AJ
Lee
Jang-Hern
JH
D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000097605:Sigma-1 Receptor
D000996:Antitussive Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D018836:Inflammation Mediators; D009025:Morpholines; D011493:Protein Kinase C; D016760:Proto-Oncogene Proteins c-fos; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C018861:carbetapentane