當組織受傷或發炎的時候，許多內源性的介質包括：前列腺素（PGE2）、血清素（5-HT)、氫離子、組織胺（Histamine）、三磷酸腺苷（ATP），會從這些部位的組織或免疫細胞釋出，誘導發炎和傷害感受的產生。5-HT是一種發炎的介質，參與調控發炎性疼痛。在週邊和中樞痛覺神經元上存在許多5-HT受體的亞型，因此研究5-HT在疼痛中的作用也相對複雜。在之前的研究中，我們發現5-HT2B/2C受體的拮抗劑可以抑制由5-HT所誘導的機械性痛覺敏感。然而，造成這種痛覺敏感所影響的神經元類型以及訊號路徑，仍然還不清楚。本篇論文的第一個部分，我證明了5-HT2B受體透過調控Gq /11β-蛋白質激酶C（PKCε）的途徑參與5-HT在小鼠中所誘導的機械性痛覺敏感。注射TRPV1的拮抗劑抑制了5-HT所造成的機械性痛覺敏感現象；而TRPV1基因剔除的小鼠在注射5-HT後也得到相同的結果。因此，5-HT2B受體透過調控TRPV1的功能，參與在血清素所引發的機械性痛覺敏感現象。
論文的第二個部分，我研究的重點是鏡像疼痛（MIP），鏡像疼痛常常在許多臨床的疾病上伴隨發生，例如複雜疼痛症候群（CRPS）、類風濕性關節炎（RA）以及慢性偏頭痛，而這類型的疼痛主要的特徵在於病人除了實際受傷或發炎的身體區域會感到疼痛，在身體對側的區域往往也會感到疼痛。已經有研究發現，嚴重的週邊組織發炎，會活化週邊或中樞神經膠質細胞，進而產生MIP。然而是哪些受體調控這些神經膠質細胞的活化，目前仍不清楚。實驗中發現，個別注射5-HT或酸性緩衝溶液到小鼠的腳掌只會產生單側疼痛，但共同注射5-HT和酸性緩衝溶液，則造成雙側的痛覺敏感現象。阻斷血清素受體3（5-HT3）和酸敏感離子通道3（ASIC3），可以降低週邊衛星膠細胞的活化，抑制MIP。值得注意的是，腳掌注射5-HT3活化劑產生的MIP，以及5-HT3受體調控的MIP，可以被5-HT3受體抑制劑或ASIC3阻斷劑所降低。使用ASIC3活化劑也發現相同的結果。此外，實驗也觀察到5-HT3受體與ASIC3在背根神經節有共同表現；5-HT3受體活化後會促進細胞內鈣離子濃度的增加，且可被ASIC3的阻斷劑所抑制，反之亦然。因此5-HT3受體與ASIC3透過彼此間的交互作用活化衛星膠細胞，進而引發鏡像疼痛。

The endogenous mediators, such as prostaglandin E2 (PGE2), bradykinin (BK), serotonin [5-hydroxytryptamine (5-HT)], proton, histamine, and ATP, are released from the damaged site of the tissue and immune cells to induce inflammation and nociception. 5-HT, an inflammatory mediator, contributes to inflammatory pain. The presence of multiple 5-HT subtype receptors on peripheral and central nociceptors complicates the role of 5-HT in pain. Previously, we found that 5-HT2B/2C antagonist blocks 5-HT-induced mechanical hyperalgesia. However, the types of neurons or circuits underlying this effect remained unsolved. In the first part of this thesis, I demonstrate that the Gq/11β-protein kinase Cε (PKCε) pathway mediated by 5-HT2B is involved in 5-HT-induced mechanical hyperalgesia in mice. Administration of a transient receptor potential vanilloid 1 (TRPV1) antagonist inhibited the 5-HT-induced mechanical hyperalgesia. Similar results were found in TRPV1-deficient mice. Thus, 5-HT2B mediates 5-HT-induced mechanical hyperalgesia by regulating TRPV1 function.

In the second part of the theis, I focus on mirror-image pain (MIP), which occurs along with complex regional pain syndrome, rheumatoid arthritis and chronic migraine, is characterized by increased pain sensitivity of healthy body regions other than the actual injured or inflamed sites. A high level of peripheral inflammation may activate central or peripheral glia, triggering mirror-image pain. However, which receptors mediate inflammatory signals to contribute glial activation remains unclear. Intraplantarly injecting mice with 5-HT or acidic buffer (proton) caused only unilateral hyperalgesia, but co-injection of 5-HT/acid induced bilateral hyperalgesia (MIP). Blocking 5-HT3 or acid-sensing ion channel 3 (ASIC3) abolished satellite glial activation, inhibiting MIP. Interestingly, intraplantar administration of a 5-HT3 agonist induced MIP, and 5-HT3–mediated MIP can be reversed by a 5-HT3 antagonist or an ASIC3 blocker. Similar results were found using ASIC3 agonist. Furthermore, 5-HT3 was observed to co-localize with ASIC3 in DRG neurons; 5-HT3 activation induced an increase in intracellular calcium that was inhibited by an ASIC3 blocker and vice versa. A cross-talk between 5-HT3 and ASIC3 mediates satellite glial activation, thereby triggering mirror-image pain.

Abbott FV, Hong Y, and Blier P. (1996) Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators. Neuropharmacology; 35: 99-110

Akopian AN, Souslova V., England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyceuz S, et al. (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci; 2: 541–548

Aley KO, Levine JD. (1999) Role of protein kinase A in the maintenance of inflammatory pain. J Neurosci; 19: 2181–6. PMID: 10066271

Aley KO, Messing RO, Mochly-Rosen D, Levine JD. (2000) Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci; 20: 4680-4685

Alvarez de la Rosa D, Canessa CM, Fyfe GK, Zhang P. (2000) Structure and regulation of amiloride-sensitive sodium channels. Annu Rev Physiol; 62: 573–594.

Alvarez de la Rosa D, Zhang P, Shao D, White F, Canessa CM. (2002) Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system. Proc Natl Acad Sci USA; 99: 2326–2331.

Basbaum AI, Bautista DM, Scherrer G, Julius D. (2009) Cellular and molecular mechanisms of pain. Cell; 139: 267-284

Beck PW and Handwerker HO. (1974) Bradykinin and serotonin effects on various types of cutaneous nerve fibres. Ptliig.Arch; 347: 209-222

Brenchat A, Romero L, García M, Pujol M, Burgueño J, Torrens A, Hamon M, Baeyens JM, Buschmann H, Zamanillo D, Vela JM. (2009) 5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice. Pain; 141: 239-247

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature; 389: 816-824

Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science; 288:306–313

Cervantes-Durán C, Vidal-Cantú GC, Barragán-Iglesias P, Pineda-Farias JB, Bravo-Hernández M, Murbartián J, Granados-Soto V. (2012) Role of peripheral and spinal 5-HT2B receptors in formalin-induced nociception. Pharmacol Biochem Behav; 102: 30-35

Cesare P, Dekker LV, Sardini A, Parker PJ, McNaughton PA. (1992) Specific involvement of PKC-ε in sensitization of the neuronal response to painful heat. Neuron; 23: 617-624

Chen CC, England S, Akopian AN, Wood JN. (1998) A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci USA; 95: 10240-10245

Chen CC, Zimmer A, Sun WH, Hall J, Brownstein MJ, Zimme A. (2002) A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc Natl Acad Sci USA; 99: 8992-8997

Chen YJ, Huang CW, Lin CS, Chang WH, Sun WH. (2009) Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain. Mol Pain; 5: 39

Chen WN, Lee CH, Lin SH, Wong CW, Sun WH, Wood JN, Chen CC (2014) Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Mol Pain 10:40

Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbum AI, Chao MV, and Julius D. (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PrdIns (4,5), P2-mediated inhibition. Nature; 411: 957-962

Cui M, Honore P, Zhong C,Gauvin D,Mikusa J, HernandezG, Chandran P, Gomtsyan A, Brown B, Bayburt EK, Marsh K, Bianchi B, McDonald H, Niforatos W, Neelands TR, Moreland RB, Decker MW, Lee CH, Sullivan JP, Faltynek CR. (2006) TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J Neurosci; 26: 9385–9393

Dai SP, Huang YH, Chang CJ, Huang YF, Hsieh WS, Tabata Y, Ishii S, and Sun WH. (2017) TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice. Scientific Reports; 7: 41415

Davis JB, Gray J, Gunthorpe M, Hatcher JP, Davey PT, Overend P, Harrles MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA. (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature; 405:183–187

Deval E, Noël J, Lay N, Alloui A, Diochot S, Friend V, Jodar M, Lazdunski M, Lingueglia E. (2008) ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J; 27: 3047-3055

Deval E, Noël J, Gasull X, Delaunay A, Alloui A, Friend V Eschalier A, Lazdunski M, Lingueglia E. (2011) Acid-sensing ion channels in postoperative pain. J Neurosci; 31: 6059-6066

Di Marzo V, Bisogno T, & De Petroellis L. Anandamide: some like it hot. (2001) Trends Pharmacol. Sci; 22: 346-349.

Dina OA, Khasar SG, Gear RW, Levine JD. (2009) Activation of Gi induces mechanical hyperalgesia poststress or inflammation. Neurosci; 160:501–507

Doak GJ, Sawynok J. (1997) Formalin-induced nociceptive behavior and edema: involvement of multiple peripheral 5-hydroxytryptamine receptor subtypes. Neurosci; 80: 939-949

Dong L, Li Z, Leffler NR, Asch AS, Chi JT, Yang LV. (2013) Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis. PLoS One; 8: e61991

Dray A, and Perkins M. (1993) Bradykinin and inflammatory pain. Trends Neurosci; 16: 99–104

Dray A. (1995) Inflammatory mediators of pain. British J Anaesthesia; 75: 125–131

England S, Bevan S, and Docherty RJ. (1996) PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurons via the cyclic AMP-protein kinase A cascade. J Physiol; 495: 429–440

Ernberg M, Lundeberg T, Kopp S. (2000) Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals. Pain; 85: 31-39

Ernberg M, Hedenberg-Magnusson B, Kurita H, Kopp S. (2006) Effects of local serotonin administration on pain and microcirculation in the human masseter muscle. J Orofac Pain; 20: 241-248

Eschalier A, Kayser V, Guilbaud G. (1989) Influence of a specific 5-HT3 antagonist on carrageenan-induced hyperalgesia in rats. Pain; 36: 249-255

Ferrari LF, Bogen O, Alessandri-Haber N, Levine E, Gear RW, Levine JD. (2012) Transient decrease in nociceptor GRK2 expression produces long-term enhancement in inflammatory pain. Neurosci; 222: 392-403

Ferrari LF, Levine E, and Levine JD. (2013) Role of a novel nociceptor autocrine mechanism in chronic pain. Eur J Neurosci; 37: 1705-1713

Fischer MJ, Btesh J, McNaughton PA. (2013) Disrupting sensitization of transient receptor potential vanilloid subtype 1 inhibits inflammatory hyperalgesia. J Neurosci; 33: 7407-14

Gavva NR, Tamir R, Qu Y, Klionsky L, Zhang TJ, Immke D, Wang J, Zhu D, Vanderah TW, Porreca F, Doherty EM, Norman MH, Wild KD, BannonAW, Louis JC, Treanor JJ. (2005) AMG9810 [(E)-3-(4- t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J Pharmacol Exp Ther; 313:474–484

Gibson HE, Edwards JG, Page RS, Van Hook MJ, Kauer JA (2008) TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron; 57:746–759

Ghilardi JR, Röhrich H, Lindsay TH, Sevcik MA, Schwei MJ, Kubota K, Halvorson KG, Poblete J, Chaplan SR, Dubin AE, Carruthers NI, Swanson D, Kuskowski M, Flores CM, Julius D, Mantyh PW. (2005) Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci; 25: 3126-3131

Giordano J, Dyche J. (1989) Differential analgesic actions of serotonin 5-HT3 receptor antagonists in the mouse. Neuropharmacology; 28: 423-427

Godínez-Chaparro B, López-Santillán FJ, Orduña P, Granados-Soto V (2012) Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT(4), 5-HT(6) and 5-HT(7) receptors. Neuroscience; 222: 379–391

Gold MS, Levine JD, Correa AM. (1998) Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J Neurosci; 18: 10345-10355

Granados-Soto V, Argüelles CF, Rocha-González HI, Godínez-Chaparro B, Flores-Murrieta FJ, Villalón CM. (2010) The role of peripheral 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F serotonergic receptors in the reduction of nociception in rats. Neurosci; 165: 561-568

Grunder S, Geissler HS, Bassler EL, & Ruppersberg JP. (2000) A new member of acid-sensing ion channels from pituitary gland. NeuroReport; 11: 1607−1611.

Honore P, Wismer CT, Mikusa J, Zhu CZ, Zhong C, Gauvin DM, Gomtsyan A, El Kouhen R, Lee CH, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF. (2005) A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats. J Pharmacol Exp Ther; 314:410–421

Hoyer D, Hannon JP, Martin GR. (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav; 71: 533-554

Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH. (2007) Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci; 36: 195-210

Hwang SW, Hawoon C, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim G, & Oh U. Proc. (2000) Nat Acad Sci USA; 97: 6155–6160.

Joseph EK, Levine JD. (2010) Multiple PKCε-dependent mechanisms mediating mechanical hyperalgesia. Pain; 150:17–21

Joseph EK, Bogen O, Alessandri-Haber N, Levine JD. (2007) PLC-beta-3 signals upstream of PKC epsilon in acute and chronic inflammatory hyperalgesia. Pain; 132:67–73

Julius D, Basbaum AI. (2001) Molecular mechanisms of nociception. Nature; 413: 203-210

Kang S, Jang JH, Price MP, Guatam M, Benson CJ, Gong H, Welsh MJ, Brennan TJ. (2012) Simultaneous Disruption of Mouse ASIC1a, ASIC2 and ASIC3 Genes Enhances Cutaneous Mechanosensitivity. Plos one; 7: 1-12

Kayser V, Elfassi IE, Aubel B, Melfort M, Julius D, Gingrich JA, Hamon M, Bourgoin S. (2007) Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. Pain; 130: 235-248

Kawabata A. (2011) Prostaglandin E2 and pain- an update. Biol Pharm Bull; 34: 1170-1173

Khasar SG, Lin YH, Martin A, Dadgar J, McMahon T, Wang D, Hundle B, Aley KO, Isenberg W, McCarter G, Green PG, Hodge CW, Levine JD, Messing RO (1999) A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice. Neuron; 24: 253–260

Kim YH, Park CK, Back SK, Lee CJ, Hwang SJ, Bae YC, Na HS, Kim JS, Jung SJ, Oh SB (2009) Membrane-delimited coupling of TRPV1 and mGluR5 on presynaptic terminals of nociceptive neurons. J Neurosci; 29:10000–10009

Kim YH, Back SK, Davies AJ, Jeong H, Jo HJ, Chung G, Na HS, Bae YC, KimSJ, Kim JS, Jung SJ, Oh SB (2012) TRPV1 in GABAergic interneurons mediates neuropathic mechanical allodynia and disinhibition of the nociceptive circuitry in the spinal cord. Neuron; 74: 640–647

Kress M, Reeh PW, Vyklicky L. (1997) An interaction of inflammatory mediators and protons in small diameter dorsal root ganglion neurons of the rat. Neurosci Lett; 224: 37-40

Krishtal OA, Pidoplichko VI. (1980) A receptor for protons in the nerve cell membrane. Neurosci; 5: 2325-2327

Lang E, Novak A, Reeh PW and Handwerker HO. (1990) Chemosensitivity of fine afferent from rat skin in vitro. J Neurophysiol; 63: 887-901

Lee YJ, Zachrisson O, Tonge DA, McNaughton PA. (2002) Upregulation of bradykinin B2 receptor expression by neurotrophic factors and nerve injury in mouse sensory neurons. Mol Cell Neurosci; 19: 186-200.

Lin SY, Chang WJ, Lin CS, Huang CY, Wang HF, and Sun WH. (2011) Serotonin receptor 5-HT2B mediates serotonin-induced mechanical hyperalgesia. J Neurosci; 31:1410–1418

Lingueglia E, de Weille JR, Bassilana F, Heurteaux C, Sakai H, Waldmann R, et al. (1997) A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J Biol Chem; 272: 29778−29783.

Liu J, Wang L, Harvey-white J, Huang BX, Kim HY, Luquet S, Palmiter RD, Krystal G, Rai R, Mahadevan A, Razdan RK, and Kunos G. (2008) Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacol; 54: 1-7.

Loric S, Maroteaux L, Kellermann O, and Launay JM. (1995) Functional serotonin-2B receptors are expressed by a teratocarcinoma-derived cell line during serotoninergic differentiation. Mol Pharmacol; 47: 458–466

Loyd DR, Chen PB, Hargreaves KM. (2012) Anti-hyperalgesic effects of anti-serotonergic compounds on serotonin- and capsaicin-evoked thermal hyperalgesia in the rat. Neurosci; 203: 207-215

Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE Junker U, Hofstetter H, Wolf RM, Seuwen K. (2003) Proton-sensing G-protein-coupled receptors. Nature; 425: 93-98

Marchand F, Perretti M, McMahon SB. (2005) Role of the immune system in chronic pain. Nat Rev Neurosci; 6: 521-532

Millan MJ. (2002) Descending control of pain. Prog Neurobiol; 66: 355-474

Molliver DC, Immke DC, Fierro L, Paré M, Rice FL, McCleske EW. (2005) ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Mol Pain; 1: 35

Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, and Tominaga M. (2005) Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain; 1: 1-13

Murakami N, Yokomizo T, Okuno T, Shimizu T. (2004) G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine. J Biol Chem; 279: 42484-42491

Narumiya S, Sugimoto Y, Ushikubi F. (1999) Prostanoid receptors: structures, properties, and functions. Physiol Rev; 79: 1193-1226

Narumiya S, FitzGerald GA. (2001) Genetic and pharmacological analysi of prostanoid receptor function. J Clin Invest; 108: 25-30

Ohta T, Ikemi Y, Murakami M, Imagawa T, Otsuguro K, Ito S. (2006) Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons. J Physiol; 576:809–822

Okun A, DeFelice M, Eyde N, Ren J, Mercado R, King T, Porreca F. (2011) Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents. Mol Pain; 7: 4

Onozawa Y, Komai T, Oda T. (2011) Activation of T cell deathassociated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells. Eur J Pharmacol; 654: 315-319

Page AJ, Brierley SM, Martin CM, Martinez-Salgado C, Wemmie JA, Brennan TJ, et al. (2004) The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. Gastroenterology; 127: 1739−1747.

Parada CA, Yeh JJ, Reichling DB, Levine JD. (2003) Transient attenuation of protein kinase Cepsilon can terminate a chronic hyperalgesic state in the rat. Neurosci; 120: 219-226

Peer LA. (1995) Transplantation of Tissues; Vol. 1.

Pertwee RG, and Ross RA. (2002) Cannabinoid receptors and their ligands. Prostaglandins Leukot. Essent. Fatty Acids; 66: 101-121

Premkumar LS, and Ahern GP. (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature; 408: 985-90

Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ. (2001) The DRASIC cation channel contributes to the detection of cutaneous ouch and acid stimuli in mice. Neuron; 32: 1071-1083

Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON. (2005) Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc Natl Acad Sci USA; 102: 1632-1637

Rahman W, Bannister K, Bee LA, Dickenson AH. (2011) A pronociceptive role for the 5-HT2 receptor on spinal nociceptive transmission: an in vivo electrophysiological study in the rat. Brain Res; 1382: 29-36

Revici E, Stoopen E, Frenk E and Ravich RA. (1949) The painful focus, II: the relation of pain to local physico-chemical changes, Bull. Inst Appl Biol; 1: 21-38

Scholz J, Woolf CJ. (2002) Can we conquer pain? Nat Neurosci; 5 Suppl: 1062-1067

Schwartz ES, La JH, Scheff NN, Davis BM, Albers KM, Gebhart GF. (2013) TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J Neurosci; 33: 5603-5611

Sekiguchi F, Aoki Y, Nakagawa M, Kanaoka D, Nishimoto Y, Tsubota-Matsunami M, Yamanaka R, Yoshida S, Kawabata A. (2013) AKAP-dependent sensitization of Ca(v) 3.2 channels via the EP(4) receptor/cAMP pathway mediates PGE(2) –induced mechanical hyperalgesia. Br J Pharmacol; 168: 734-745

Sluka KA, Price MP, Breese NM, Stucky CL, Wemmie JA, Welsh MJ. (2003) Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain; 106: 229-239

Sluka KA, Radhakrishnan R, Benson CJ, Eshcol JO, Pric MP, Babinski K, Audette KM, Yeomans DC, Wilson SP. (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain; 129: 102-112

Song Z, Meyerson BA, Linderoth B. (2011) Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy. Pain; 152: 1666-1673

Sommer C. (2004) Serotonin in pain and analgesia. In: Bazan NG, and Mallet J (eds) Mol neurobiol; vol. 30. Humana Press Inc. pp. 117–125

Steen KH, Reeh PW. (1993) Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin. Neurosci Lett; 154: 113-116

Steen KH, Issberner U, Reeh PW. (1995) Pain due to experimental acidosis in human skin: evidence for non-adapting nociceptor excitation. Neurosci Lett; 199: 29-32

Steen KH, Steen AE, Kreysel HW, Reeh PW. (1996) Inflammatory mediators potentiate pain induced by experimental tissue acidosis. Pain; 66: 163-170

Sufka KJ, Schomburg FM, Giordano J. (1992) Receptor mediation of 5-HT-induced inflammation and nociception in rats. Pharmacol Biochem Behav; 41: 53-56

Sugiuar T, Bielefeldt K, Gebhart GF (2004) TRPV1 function in mouse colon sensory neurons is enhanced by metabotropic 5-hydroxytryptamine receptor activation. J Neurosci; 24:9521–9530

Tappe-Theodor A, Constantin CE, Tegeder I, Lechner SG, Langeslag M, Lepcynzsky P, Wirotanseng RI, Kurejova M, Agarwal N, Nagy G, Todd A, Wettschureck N, Offermanns S, Kress M, Lewin GR, Kuner R (2012) Gα(q/11) signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization. Pain; 153:184–196

Taiwo YO and Levine JD. (1992) Serotonin is a directly-acting hyperalgesic agent in the rat. Neurosci; 48: 485-490

Tokunaga A, Saika M, Senba E. (1998) 5-HT2A receptor subtype is involved in the thermal hyperalgesic mechanism of serotonin in the periphery. Pain; 76: 349-355

Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D. (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron; 21: 531-543

Tournois C, Mutel V, Manivet P, Launay JM, and Kellermann O. (1998) Cross-talk between 5-hydroxytryptamine receptors in a serotonergic cell line. J Biol Chem; 273: 17498-17503.

Urtikova N, Berson N, Van Steenwinckel J, Doly S, Truchetto J, Maroteaux L, Pohl M, Conrath M. (2012) Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain. Pain; 153:1320–1331

Walder RY, Ramussen LA, Rainier JD, Light AR, Wemmie JA, and Sluka KA. (2010) ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury. J Pain; 11: 210−218

Walder RY, Radhakrishnan R, Loo L, Rasmussen LA, Mohapatra DP, Wilson SP, Sluka KA. (2012) TRPV1 is important for mechanical and heat sensitivity in uninjured animals and development of heat hypersensitivity after muscle inflammation. Pain; 153: 1664-1672

Waldmann R, Bassilana F, de Weille J, Champigny G, Heurteaux C, Lazdunski M. (1997a) Molecular cloning of a noninactivating proton-gated Na+ channel specific for sensory neurons. J Biol Chem; 272: 20975-20978

Waldmann R, Champigny G, Bassilana F, Heurteaux C Lazdunski M. (1997b) A proton-gated cation channel involved in acid-sensing. Nature; 386: 173-177

Waldmann R, & Lazdunski M. (1998) H(+)-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr Opin Neurobiol; 8:418–424.

Wang JQ, Kon J, Mogi C, Tobo M, Damirin A, Sato K, Komachi M, Malchinkhuu E, Murata N, Kimura T, Kuwabara A, Wakamatsu K, Koizumi H, Uede T, Tsujimoto G, Kurose H, Sato T, Harada A, Misawa N, Tomura H, Okajima F. (2004) TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. J Biol Chem; 279: 45626-45633

Wang C, Gu Y, Li GW, Huang LY. (2007) A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. J Physiol; 584: 191-203

Wang C, Li GW, Huang LY. (2007) Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons. Mol Pain; 3: 22

Wang D, Chen T, Gao Y, Quirion R, Hong Y. (2012) Inhibition of SNL-induced upregulation of CGRP and NPY in the spinal cord and dorsal root ganglia by the 5-HT(2A) receptor antagonist ketanserin in rats. Pharmacol Biochem Behav; 101: 379-386

Wood JN et al. (1998) Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J Neurosci; 8: 3208-3220.

Wu WL, Cheng CF, Sun WH, Wong CW, Chen CC. (2012) Target ASIC3 for pain, anxiety, and insulin resistance. Pharmacol and Therapeutic; 134: 127-138.

Yu L, Yang F, Luo H, Liu FY, Han JS, Xing GG, Wan Y. (2008) The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund’s adjuvant. Mol Pain; 4: 61

Yu Y, Chen Z, Li WG, Cao H, Feng EG, Yu F, Liu H, Jiang H, and Xu TL. (2010) A nonproton ligand sensor in the acid-sensing ion channel. Neuron; 68: 61-72

Zeitz KP, Guy N, Malmberg AB, Dirajlal S, Martin WJ, Sun L, Bonhaus DW, Stucky CL, Julius D, Basbaum AI. (2002) The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J Neurosci; 22: 1010-1019