Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons.
B-type natriuretic peptide (BNP) has been known to be secreted from cardiac myocytes and activate its receptor, natriuretic peptide receptor-A (NPR-A), to reduce ventricular fibrosis. However, the function of BNP/NPR-A pathway in the somatic sensory system has been unknown. In the present study, we report a novel function of BNP in pain modulation. Using microarray and immunoblot analyses, we found that BNP and NPR-A were expressed in the dorsal root ganglion (DRG) of rats and upregulated after intraplantar injection of complete Freund's adjuvant (CFA). Immunohistochemistry showed that BNP was expressed in calcitonin gene-related peptide (CGRP)-containing small neurons and IB4 (isolectin B4)-positive neurons, whereas NPR-A was present in CGRP-containing neurons. Application of BNP reduced the firing frequency of small DRG neurons in the presence of glutamate through opening large-conductance Ca2+-activated K+ channels (BKCa channels). Furthermore, intrathecal injection of BNP yielded inhibitory effects on formalin-induced flinching behavior and CFA-induced thermal hyperalgesia in rats. Blockade of BNP signaling by BNP antibodies or cGMP-dependent protein kinase (PKG) inhibitor KT5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester] impaired the recovery from CFA-induced thermal hyperalgesia. Thus, BNP negatively regulates nociceptive transmission through presynaptic receptor NPR-A, and activation of the BNP/NPR-A/PKG/BKCa channel pathway in nociceptive afferent neurons could be a potential strategy for inflammatory pain therapy.
Zhang
Fang-Xiong
FX
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Liu
Xing-Jun
XJ
Gong
Li-Qin
LQ
Yao
Jun-Ru
JR
Li
Kai-Cheng
KC
Li
Zi-Yan
ZY
Lin
Li-Bo
LB
Lu
Ying-Jin
YJ
Xiao
Hua-Sheng
HS
Bao
Lan
L
Zhang
Xiao-Hui
XH
Zhang
Xu
X
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D055592:Biophysical Phenomena / Q000187:drug effects / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000494:pharmacology; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D037102:Lectins / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000276:immunology / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D000906:Antibodies; D002227:Carbazoles; D004791:Enzyme Inhibitors; D037102:Lectins; D010455:Peptides; D020097:Natriuretic Peptide, Brain; C073601:KT 5823; D018698:Glutamic Acid; C064719:iberiotoxin; D005620:Freund's Adjuvant; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D015740:Calcitonin Gene-Related Peptide