TY - JOUR
T1 - Kainate-induced excitation and sensitization of nociceptors in normal and inflamed rat glabrous skin
AU - Du, J.
AU - Zhou, S.
AU - Carlton, S. M.
N1 - Funding Information:
The authors thank Zhixia Ding for assistance in the immunohistochemistry and electron microscopy and Vicki Wilson for her excellent secretarial assistance. This work was supported by NS27910, NS40700 and NS11255 to SMC.
PY - 2006
Y1 - 2006
N2 - This study investigates contributions of peripheral kainate receptors to acute nociception and persistent inflammatory pain in rat. Immunohistochemical analysis of kainate receptor expression using antibodies recognizing glutamate receptor subunits 5, 6, and 7 demonstrates that 28% of unmyelinated axons in normal digital nerve are positively labeled. Following intraplantar injection of complete Freund's adjuvant, a significant increase in glutamate receptor subunits 5, 6, and 7-labeled axons occurs at 2 days (40%), but not 7 (31%) or 14 days (28%) post-complete Freund's adjuvant. In behavioral studies, we confirm an increased mechanical sensitivity in complete Freund's adjuvant-injected hind paws. Furthermore, activation of kainate receptors following intraplantar injection of 1.0mM kainate in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. A 1.0mM kainate injection into inflamed hind paws further enhances the mechanical sensitivity. Injection of the non-N-methyl-d-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3- dione (0.1mM) reverses complete Freund's adjuvant-induced mechanical sensitivity through a local effect. In single unit recordings from nociceptors in a glabrous skin-nerve preparation, mechanical sensitization is present in inflamed skin evidenced by a decrease in mechanical threshold and an increase in discharge rate during a suprathreshold, constant force stimulus. Thermal sensitization is also present evidenced by a decrease in heat threshold. There is a dose-dependent increase in kainate-induced nociceptor activity in both normal and inflamed skin but the kainate required to induce activation is reduced in inflamed skin. Although proportions of kainate-activated nociceptors are the same in normal and inflamed skin, the kainate-induced mean discharge rate is significantly enhanced in inflamed skin. Exposure of normal and inflamed nociceptors to 0.3mM kainate sensitizes fibers to re-application of kainate and heat. This sensitization is blocked in the presence of 6-cyano-7- nitroquinoxaline-2,3-dione or the glutamate receptor subunit 5 selective antagonist 3S,4aR,6S,8aR-6-[4-carboxy-phenyl] methyl-1,2,3,4,4a,5,6,7,8,8a-deca- hydroisoquinoline-3-carboxylic acid. The data indicate that peripheral kainate receptors not only play an important role in normal nociception but also contribute to mechanical sensitivity and heat sensitization accompanying inflammatory pain.
AB - This study investigates contributions of peripheral kainate receptors to acute nociception and persistent inflammatory pain in rat. Immunohistochemical analysis of kainate receptor expression using antibodies recognizing glutamate receptor subunits 5, 6, and 7 demonstrates that 28% of unmyelinated axons in normal digital nerve are positively labeled. Following intraplantar injection of complete Freund's adjuvant, a significant increase in glutamate receptor subunits 5, 6, and 7-labeled axons occurs at 2 days (40%), but not 7 (31%) or 14 days (28%) post-complete Freund's adjuvant. In behavioral studies, we confirm an increased mechanical sensitivity in complete Freund's adjuvant-injected hind paws. Furthermore, activation of kainate receptors following intraplantar injection of 1.0mM kainate in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. A 1.0mM kainate injection into inflamed hind paws further enhances the mechanical sensitivity. Injection of the non-N-methyl-d-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3- dione (0.1mM) reverses complete Freund's adjuvant-induced mechanical sensitivity through a local effect. In single unit recordings from nociceptors in a glabrous skin-nerve preparation, mechanical sensitization is present in inflamed skin evidenced by a decrease in mechanical threshold and an increase in discharge rate during a suprathreshold, constant force stimulus. Thermal sensitization is also present evidenced by a decrease in heat threshold. There is a dose-dependent increase in kainate-induced nociceptor activity in both normal and inflamed skin but the kainate required to induce activation is reduced in inflamed skin. Although proportions of kainate-activated nociceptors are the same in normal and inflamed skin, the kainate-induced mean discharge rate is significantly enhanced in inflamed skin. Exposure of normal and inflamed nociceptors to 0.3mM kainate sensitizes fibers to re-application of kainate and heat. This sensitization is blocked in the presence of 6-cyano-7- nitroquinoxaline-2,3-dione or the glutamate receptor subunit 5 selective antagonist 3S,4aR,6S,8aR-6-[4-carboxy-phenyl] methyl-1,2,3,4,4a,5,6,7,8,8a-deca- hydroisoquinoline-3-carboxylic acid. The data indicate that peripheral kainate receptors not only play an important role in normal nociception but also contribute to mechanical sensitivity and heat sensitization accompanying inflammatory pain.
KW - Complete Freund's adjuvant
KW - Glutamate
KW - Inflammation
KW - Kainate acid
KW - Pain
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U2 - 10.1016/j.neuroscience.2005.10.008
DO - 10.1016/j.neuroscience.2005.10.008
M3 - Article
C2 - 16330152
AN - SCOPUS:30144438034
SN - 0306-4522
VL - 137
SP - 999
EP - 1013
JO - Neuroscience
JF - Neuroscience
IS - 3
ER -