Depletion of capsaicin-sensitive afferents prevents lamina-dependent increases in spinal N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation associated with thermal hyperalgesia in neuropathic rats.
Phosphorylation of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit (pNR1) in the spinal cord is associated with increased neuronal responsiveness, which underlies the process of central sensitization. Because of the importance of NR1 in central sensitization, the first goal of this study was to examine both time- and lamina-dependent changes in spinal NR1 and pNR1 expression in a chronic constriction injury (CCI) model of neuropathic pain. Increased excitability of capsaicin sensitive primary afferents (CSPAs), which express TRPV1 receptors, also contributes to central sensitization. Thus, we next examined whether the depletion of CSPAs with resiniferatoxin (RTX) modified the change of spinal NR1 and pNR1 expression induced by CCI. Experimental rats were euthanized at 1, 3, 7, 14, and 28 days post-CCI surgery and spinal cords processed for NR1 or pNR1 immunostaining. The number of NR1 or pNR1-immunoreactive neurons was significantly increased in all lamina (I-VI) of the ipsilateral L4/L5 dorsal horn from 1 or 7 days post-CCI, respectively. Pretreatment with RTX (0.3mg/kg, s.c. in the scruff of the neck or intraplantar) 2 days prior to CCI completely prevented induction of thermal hyperalgesia, but not mechanical allodynia in neuropathic rats. Interestingly, RTX treatment significantly attenuated the CCI-induced upregulation of NR1 and pNR1 in spinal laminae I-II and V-VI, but not laminae III-IV as compared with that of vehicle-treated CCI rats. These findings demonstrate that the increased expression of NR1 and pNR1 in spinal laminae I-II and V-VI is dependent on activation of CSPAs, which ultimately contribute to the development of thermal hyperalgesia in neuropathic rats.
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
Han
Ho-Jae
HJ
Beitz
Alvin J
AJ
Lee
Jang-Hern
JH
D000344:Afferent Pathways / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D008026:Ligation; D008297:Male; D010465:Perception; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000502:physiology*; D011312:Pressure / Q000009:adverse effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000503:physiopathology*; D013116:Spinal Cord / Q000503:physiopathology*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D002211:Capsaicin; D004224:Diterpenes; D016194:Receptors, N-Methyl-D-Aspartate; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C024353:resiniferatoxin