TY - JOUR
T1 - Blockade of peripheral and spinal Na+/H+ exchanger increases formalin-induced long-lasting mechanical allodynia and hyperalgesia in rats
AU - Castañeda-Corral, Gabriela
AU - Rocha-González, Héctor I.
AU - Araiza-Saldaña, Claudia I.
AU - Vidal-Cantú, Guadalupe C.
AU - Jiménez-Andrade, Juan Miguel
AU - Murbartián, Janet
AU - Granados-Soto, Vinicio
N1 - Funding Information:
Gabriela Castañeda-Corral is a Conacyt fellow. This work is part of the Ph.D. dissertation of Gabriela Castañeda-Corral. Partially supported by Conacyt , grant 59879 (VG-S) . Vinicio Granados-Soto is a visiting professor at the Department of Pharmacology, School of Medicine of Ribeirão Preto, University of Sao Paulo, Brazil. Support by CNPq is kindly acknowledged.
PY - 2012/9/26
Y1 - 2012/9/26
N2 - The Na/H exchanger (NHE) is involved in the regulation of intracellular pH and volume by mediating the electroneutral transport of H against an influx of Na ions. Since NHE1 regulates pH in neurons and astrocytes and it is expressed in nociceptive nerve fibers, it is likely that NHE may modulate neuronal excitability and pain transmission. The purpose of this study was to assess the participation of peripheral and spinal NHE in the secondary allodynia/ hyperalgesia induced by formalin. In addition, we determined whether formalin injection modifies the expression of NHE1 in lumbar dorsal root ganglia (DRG) and dorsal spinal cord. Subcutaneous injection of 0.5% formalin into the dorsal surface of the hind paw produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-lasting bilateral secondary mechanical allodynia/hyperalgesia. Peripheral and intrathecal pre-treatment (-10 min) with selective NHE inhibitors 5-(N,N-dimethyl)amiloride hydrochloride (DMA, 0.3-30 μM), 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 0.3-30 μM) and [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine dihydrochloride (zoniporide, 0.03-3 μM) significantly increased 0.5% formalin-induced bilateral long-lasting secondary allodynia/hyperalgesia. Contrariwise, local peripheral or intrathecal post-treatment (day 6 postinjection) with these NHE inhibitors did not affect formalin-induced nociceptive behaviors. Formalin injection reduced NHE1 expression in ipsilateral and contralateral spinal dorsal horns from day 1 to 12. In addition, formalin diminished NHE1 protein expression in DRG at day 12. These results suggest that NHE1 plays a role in pain processing at peripheral and spinal levels in formalin-induced long-lasting nociceptive behaviors. Additionally, these results suggest that proteins involved in pH regulation could be targets for the development of new analgesic drugs.
AB - The Na/H exchanger (NHE) is involved in the regulation of intracellular pH and volume by mediating the electroneutral transport of H against an influx of Na ions. Since NHE1 regulates pH in neurons and astrocytes and it is expressed in nociceptive nerve fibers, it is likely that NHE may modulate neuronal excitability and pain transmission. The purpose of this study was to assess the participation of peripheral and spinal NHE in the secondary allodynia/ hyperalgesia induced by formalin. In addition, we determined whether formalin injection modifies the expression of NHE1 in lumbar dorsal root ganglia (DRG) and dorsal spinal cord. Subcutaneous injection of 0.5% formalin into the dorsal surface of the hind paw produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-lasting bilateral secondary mechanical allodynia/hyperalgesia. Peripheral and intrathecal pre-treatment (-10 min) with selective NHE inhibitors 5-(N,N-dimethyl)amiloride hydrochloride (DMA, 0.3-30 μM), 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 0.3-30 μM) and [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine dihydrochloride (zoniporide, 0.03-3 μM) significantly increased 0.5% formalin-induced bilateral long-lasting secondary allodynia/hyperalgesia. Contrariwise, local peripheral or intrathecal post-treatment (day 6 postinjection) with these NHE inhibitors did not affect formalin-induced nociceptive behaviors. Formalin injection reduced NHE1 expression in ipsilateral and contralateral spinal dorsal horns from day 1 to 12. In addition, formalin diminished NHE1 protein expression in DRG at day 12. These results suggest that NHE1 plays a role in pain processing at peripheral and spinal levels in formalin-induced long-lasting nociceptive behaviors. Additionally, these results suggest that proteins involved in pH regulation could be targets for the development of new analgesic drugs.
KW - Chronic pain
KW - NHE inhibitors
KW - NHE1
KW - Protons
KW - Secondary allodynia
KW - Secondary hyperalgesia
UR - http://www.scopus.com/inward/record.url?scp=84865751665&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2012.08.001
DO - 10.1016/j.brainres.2012.08.001
M3 - Artículo
SN - 0006-8993
VL - 1475
SP - 19
EP - 30
JO - Brain Research
JF - Brain Research
ER -