Substance P sensitizes P2X3 in nociceptive trigeminal neurons.
Peripheral inflammation produces pain hypersensitivity by sensitizing nociceptors. Potentiation of P2X3 receptor activity in nociceptors may play an important role in this peripheral sensitization. However, we do not fully understand how P2X3 activity is elevated in inflammation. Thus, we investigated whether P2X3 activity in trigeminal nociceptive neurons is regulated by the neurokinin-1 (NK-1) receptor that is activated by an inflammatory mediator, substance P. Single-cell RT-PCR and immunohistochemistry revealed that NK-1 in nociceptive neurons was mainly co-expressed with P2X3. Ca(2+) imaging and whole-cell patch-clamp recordings indicated that both substance P and Sar-substance P, a selective NK-1 agonist, significantly potentiated α,β-meATP-induced currents and [Ca(2+)](i) responses in nociceptive neurons. These potentiating effects were completely blocked by GR82334, a specific NK-1 antagonist. Our results demonstrate that substance P sensitizes P2X3 receptor through the activation of NK-1, thus warranting these receptors as possible targets for pain therapy in the orofacial region.


BACKGROUND
α,β-methylene adenosine 5'-triphosphate (ATP), α,β-meATP; neurokinin-1, NK-1; single-cell reverse-transcription polymerase chain-reaction, single-cell RT-PCR; [Sar(9),Met(O(2))(11)]-substance P, Sar-substance P.
Park
C K
CK
National Research Laboratory for Pain, Dental Research Institute and Department of Physiology, School of Dentistry, Seoul National University, 28-2 Yeongeon-Dong Chongno-Ku, Seoul 110-749, Republic of Korea.
Bae
J H
JH
Kim
H Y
HY
Jo
H J
HJ
Kim
Y H
YH
Jung
S J
SJ
Kim
J S
JS
Oh
S B
SB
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000187:drug effects; D003592:Cytophotometry; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects*; D009619:Nociceptors / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000187:drug effects; D018048:Receptors, Purinergic P2 / Q000187:drug effects*; D058477:Receptors, Purinergic P2X3; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*; D014276:Trigeminal Nerve / Q000187:drug effects*
D018836:Inflammation Mediators; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; C062618:substance P, Sar(9)-Met(O2)(11)-; C079014:GR 82334; D010803:Physalaemin; D013373:Substance P; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate