Advertisement

Molecular Neurobiology

, Volume 56, Issue 8, pp 5715–5728 | Cite as

Non-Peptidergic Nociceptive Neurons Are Essential for Mechanical Inflammatory Hypersensitivity in Mice

  • Larissa G. Pinto
  • Guilherme R. Souza
  • Ricardo Kusuda
  • Alexandre H. Lopes
  • Morena B. Sant’Anna
  • Fernando Q. Cunha
  • Sérgio H. Ferreira
  • Thiago M. CunhaEmail author
Article
  • 523 Downloads

Abstract

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

Keywords

Non-peptidergic C-fibers IB4-saporin Mechanical hypersensitivity Inflammatory pain Nociceptors Mice 

Abbreviations

ATF-3

Activating transcription factor 3

AUC

Area under the curve

BSA

Bovine serum albumin

cAMP

Cyclic adenosine monophosphate

CGRP

Calcitonin-gene related peptide

DRG

Dorsal root ganglion

EP

E prostanoid receptor

g

Grams

GDNF

Glial cell-derived neurotrophic factor

GFRα-1

GDNF family receptor alpha 1

GPCR

G protein-coupled receptor

HCN

Hyperpolarization-activated cyclic nucleotide-gated

HTMRs

High-threshold mechanoreceptors

IB4

Isolectin B4

IB4-Sap

IB4-saporin

i.pl.

Intraplantar

i.t.

Intrathecal

LTMRs

Low-threshold mechanoreceptors

MCP-1

Monocyte chemoattractant protein 1

Nav

Voltage-gated sodium ion channel

NGF

Nerve growth factor

OCT

Optimum cutting temperature

PBS

Phosphate-buffered saline

P2X3

Purinoceptor 3

PFA

Paraformaldehyde

PGE2

Prostaglandin E2

PKA

Protein kinase A

PKCε

Epsilon isozyme of protein kinase C

Sap

Unconjugated saporin

SEM

Standard error of the mean

T-PER

Tissue protein extraction reagent

TrkA

Tropomyosin receptor kinase A

TRPV1

Transient receptor potential cation channel subfamily V member 1

WT

Wild type

Notes

Acknowledgments

We thank Ieda Regina dos Santos Schivo, Sérgio Roberto Rosa, Eleni Luiza Tamburus Gomes, Elizabete Rosa, and Ana Kátia dos Santos for their excellent technical assistance.

Funding Information

The research leading to these results received funding from the São Paulo Research Foundation (FAPESP) under grant agreements number 2011/19670–0 (Thematic project) and 2013/08216–2 (Centre for Research in Inflammatory Disease), from the University of São Paulo NAP-DIN under grant agreement number 11.1.21625.01.0 and from a CNPq grant number 485177/2012-9. L.G.P. was supported by doctoral fellowship from FAPESP under grant number 2010/04043-8.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Basbaum A, Jessel T (2000) The perception of pain. Principles of neural science, fourth edition edn. McGraw-Hill, New YorkGoogle Scholar
  2. 2.
    Meyer R, Ringkamp M, Campbell J, Raja S (2013) Peripheral mechanisms of cutaneous nociception. Wall and Melzack's textbook of pain, Sixth edn. Elsevier, PhiladelphiaGoogle Scholar
  3. 3.
    Snider WD, McMahon SB (1998) Tackling pain at the source: new ideas about nociceptors. Neuron 20(4):629–632PubMedCrossRefGoogle Scholar
  4. 4.
    Molliver DC, Radeke MJ, Feinstein SC, Snider WD (1995) Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections. J Comp Neurol 361(3):404–416.  https://doi.org/10.1002/cne.903610305 PubMedCrossRefGoogle Scholar
  5. 5.
    Verge VM, Richardson PM, Benoit R, Riopelle RJ (1989) Histochemical characterization of sensory neurons with high-affinity receptors for nerve growth factor. J Neurocytol 18(5):583–591PubMedCrossRefGoogle Scholar
  6. 6.
    Verge VM, Riopelle RJ, Richardson PM (1989) Nerve growth factor receptors on normal and injured sensory neurons. J Neurosci 9(3):914–922PubMedCrossRefGoogle Scholar
  7. 7.
    Bennett DL, Michael GJ, Ramachandran N, Munson JB, Averill S, Yan Q, McMahon SB, Priestley JV (1998) A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci 18(8):3059–3072PubMedCrossRefGoogle Scholar
  8. 8.
    Molliver DC, Snider WD (1997) Nerve growth factor receptor TrkA is down-regulated during postnatal development by a subset of dorsal root ganglion neurons. J Comp Neurol 381(4):428–438PubMedCrossRefGoogle Scholar
  9. 9.
    Molliver DC, Wright DE, Leitner ML, Parsadanian AS, Doster K, Wen D, Yan Q, Snider WD (1997) IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19(4):849–861PubMedCrossRefGoogle Scholar
  10. 10.
    Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45(1):17–25.  https://doi.org/10.1016/j.neuron.2004.12.015 PubMedCrossRefGoogle Scholar
  11. 11.
    Tarpley JW, Kohler MG, Martin WJ (2004) The behavioral and neuroanatomical effects of IB4-saporin treatment in rat models of nociceptive and neuropathic pain. Brain Res 1029(1):65–76.  https://doi.org/10.1016/j.brainres.2004.09.027 PubMedCrossRefGoogle Scholar
  12. 12.
    Bogen O, Dina OA, Gear RW, Levine JD (2009) Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican. Neuroscience 159(2):780–786.  https://doi.org/10.1016/j.neuroscience.2008.12.049 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Joseph EK, Levine JD (2010) Hyperalgesic priming is restricted to isolectin B4-positive nociceptors. Neuroscience 169(1):431–435.  https://doi.org/10.1016/j.neuroscience.2010.04.082 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Alvarez P, Gear RW, Green PG, Levine JD (2012) IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat. Exp Neurol 233(2):859–865.  https://doi.org/10.1016/j.expneurol.2011.12.019 PubMedCrossRefGoogle Scholar
  15. 15.
    Joseph EK, Chen X, Bogen O, Levine JD (2008) Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain 9(5):463–472.  https://doi.org/10.1016/j.jpain.2008.01.335 PubMedCrossRefGoogle Scholar
  16. 16.
    Ye Y, Dang D, Viet CT, Dolan JC, Schmidt BL (2012) Analgesia targeting IB4-positive neurons in cancer-induced mechanical hypersensitivity. J Pain 13(6):524–531.  https://doi.org/10.1016/j.jpain.2012.01.006 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    La JH, Feng B, Kaji K, Schwartz ES, Gebhart GF (2016) Roles of isolectin B4-binding afferents in colorectal mechanical nociception. Pain 157(2):348–354.  https://doi.org/10.1097/j.pain.0000000000000380 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Ye Y, Bae SS, Viet CT, Troob S, Bernabé D, Schmidt BL (2014) IB4(+) and TRPV1(+) sensory neurons mediate pain but not proliferation in a mouse model of squamous cell carcinoma. Behav Brain Funct 10:5.  https://doi.org/10.1186/1744-9081-10-5 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67(2–3):313–316PubMedCrossRefGoogle Scholar
  20. 20.
    Cunha TM, Verri WA, Vivancos GG, Moreira IF, Reis S, Parada CA, Cunha FQ, Ferreira SH (2004) An electronic pressure-meter nociception paw test for mice. Braz J Med Biol Res 37(3):401–407PubMedCrossRefGoogle Scholar
  21. 21.
    Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63PubMedCrossRefGoogle Scholar
  22. 22.
    Sakurada T, Katsumata K, Tan-No K, Sakurada S, Kisara K (1992) The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord. Neuropharmacology 31(12):1279–1285PubMedCrossRefGoogle Scholar
  23. 23.
    Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387(6632):505–508.  https://doi.org/10.1038/387505a0 PubMedCrossRefGoogle Scholar
  24. 24.
    Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K, Yonenobu K, Ochi T et al (2000) Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: a novel neuronal marker of nerve injury. Mol Cell Neurosci 15(2):170–182.  https://doi.org/10.1006/mcne.1999.0814 PubMedCrossRefGoogle Scholar
  25. 25.
    Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139(2):267–284.  https://doi.org/10.1016/j.cell.2009.09.028 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ferreira SH, Nakamura M, de Abreu Castro MS (1978) The hyperalgesic effects of prostacyclin and prostaglandin E2. Prostaglandins 16(1):31–37PubMedCrossRefGoogle Scholar
  27. 27.
    Khasar SG, McCarter G, Levine JD (1999) Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors. J Neurophysiol 81(3):1104–1112PubMedCrossRefGoogle Scholar
  28. 28.
    Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413(6852):203–210.  https://doi.org/10.1038/35093019 PubMedCrossRefGoogle Scholar
  29. 29.
    Kandel E, Schwartz JH, Jessell T (2012) Principles of neural sciences, Fifth edn. McGraw-Hill, New YorkGoogle Scholar
  30. 30.
    Woolf CJ, Ma Q (2007) Nociceptors--noxious stimulus detectors. Neuron 55(3):353–364.  https://doi.org/10.1016/j.neuron.2007.07.016 PubMedCrossRefGoogle Scholar
  31. 31.
    Nishiguchi J, Sasaki K, Seki S, Chancellor MB, Erickson KA, de Groat WC, Kumon H, Yoshimura N (2004) Effects of isolectin B4-conjugated saporin, a targeting cytotoxin, on bladder overactivity induced by bladder irritation. Eur J Neurosci 20(2):474–482.  https://doi.org/10.1111/j.1460-9568.2004.03508.x PubMedCrossRefGoogle Scholar
  32. 32.
    Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA et al (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278(5336):275–279PubMedCrossRefGoogle Scholar
  33. 33.
    Wiley RG, Lappi DA (2003) Targeted toxins in pain. Adv Drug Deliv Rev 55(8):1043–1054PubMedCrossRefGoogle Scholar
  34. 34.
    Vulchanova L, Olson TH, Stone LS, Riedl MS, Elde R, Honda CN (2001) Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neuroscience 108(1):143–155PubMedCrossRefGoogle Scholar
  35. 35.
    Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12(4–5):256–268.  https://doi.org/10.1006/mcne.1998.0719 PubMedCrossRefGoogle Scholar
  36. 36.
    Hai T, Hartman MG (2001) The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene 273(1):1–11PubMedCrossRefGoogle Scholar
  37. 37.
    Albers KM, Woodbury CJ, Ritter AM, Davis BM, Koerber HR (2006) Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors. J Neurosci 26(11):2981–2990.  https://doi.org/10.1523/JNEUROSCI.4863-05.2006 PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Bogen O, Joseph EK, Chen X, Levine JD (2008) GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican. Eur J Neurosci 28(1):12–19.  https://doi.org/10.1111/j.1460-9568.2008.06308.x PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309.  https://doi.org/10.1038/nrn1078 PubMedCrossRefGoogle Scholar
  40. 40.
    Malik-Hall M, Dina OA, Levine JD (2005) Primary afferent nociceptor mechanisms mediating NGF-induced mechanical hyperalgesia. Eur J Neurosci 21(12):3387–3394.  https://doi.org/10.1111/j.1460-9568.2005.04173.x PubMedCrossRefGoogle Scholar
  41. 41.
    Delmas P, Hao J, Rodat-Despoix L (2011) Molecular mechanisms of mechanotransduction in mammalian sensory neurons. Nat Rev Neurosci 12(3):139–153.  https://doi.org/10.1038/nrn2993 PubMedCrossRefGoogle Scholar
  42. 42.
    Lumpkin EA, Caterina MJ (2007) Mechanisms of sensory transduction in the skin. Nature 445(7130):858–865.  https://doi.org/10.1038/nature05662 PubMedCrossRefGoogle Scholar
  43. 43.
    Löken LS, Wessberg J, Morrison I, McGlone F, Olausson H (2009) Coding of pleasant touch by unmyelinated afferents in humans. Nat Neurosci 12(5):547–548.  https://doi.org/10.1038/nn.2312 PubMedCrossRefGoogle Scholar
  44. 44.
    Perl ER (1996) Cutaneous polymodal receptors: characteristics and plasticity. Prog Brain Res 113:21–37PubMedCrossRefGoogle Scholar
  45. 45.
    Arcourt A, Gorham L, Dhandapani R, Prato V, Taberner FJ, Wende H, Gangadharan V, Birchmeier C et al (2017) Touch receptor-derived sensory information alleviates acute pain signaling and fine-tunes nociceptive reflex coordination. Neuron 93(1):179–193.  https://doi.org/10.1016/j.neuron.2016.11.027 PubMedCrossRefGoogle Scholar
  46. 46.
    Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH (2009) Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462(7273):651–655.  https://doi.org/10.1038/nature08505 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kim SE, Coste B, Chadha A, Cook B, Patapoutian A (2012) The role of Drosophila Piezo in mechanical nociception. Nature 483(7388):209–212.  https://doi.org/10.1038/nature10801 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, Mathur J, Bégay V et al (2014) Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516(7529):121–125.  https://doi.org/10.1038/nature13980 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Saeed AW, Pawlowski SA, Ribeiro-da-Silva A (2015) Limited changes in spinal lamina I dorsal horn neurons following the cytotoxic ablation of non-peptidergic C-fibers. Mol Pain 11:54.  https://doi.org/10.1186/s12990-015-0060-z PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Taylor AM, Osikowicz M, Ribeiro-da-Silva A (2012) Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain. Pain 153(6):1311–1319.  https://doi.org/10.1016/j.pain.2012.03.023 PubMedCrossRefGoogle Scholar
  51. 51.
    Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, Nassar MA, Dickenson AH et al (2008) The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321(5889):702–705.  https://doi.org/10.1126/science.1156916 PubMedCrossRefGoogle Scholar
  52. 52.
    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(6653):816–824.  https://doi.org/10.1038/39807 PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI et al (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288(5464):306–313PubMedCrossRefGoogle Scholar
  54. 54.
    Breese NM, George AC, Pauers LE, Stucky CL (2005) Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse. Pain 115(1–2):37–49.  https://doi.org/10.1016/j.pain.2005.02.010 PubMedCrossRefGoogle Scholar
  55. 55.
    Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI et al (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21(3):531–543PubMedCrossRefGoogle Scholar
  56. 56.
    Tena B, Escobar B, Arguis MJ, Cantero C, Rios J, Gomar C (2012) Reproducibility of electronic Von Frey and Von Frey monofilaments testing. Clin J Pain 28(4):318–323.  https://doi.org/10.1097/AJP.0b013e31822f0092 PubMedCrossRefGoogle Scholar
  57. 57.
    Zimmerman A, Bai L, Ginty DD (2014) The gentle touch receptors of mammalian skin. Science 346(6212):950–954.  https://doi.org/10.1126/science.1254229 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Dai Y, Fukuoka T, Wang H, Yamanaka H, Obata K, Tokunaga A, Noguchi K (2004) Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons. Pain 108(3):258–266.  https://doi.org/10.1016/j.pain.2003.12.034 PubMedCrossRefGoogle Scholar
  59. 59.
    Honore P, Kage K, Mikusa J, Watt AT, Johnston JF, Wyatt JR, Faltynek CR, Jarvis MF et al (2002) Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain 99(1–2):11–19PubMedCrossRefGoogle Scholar
  60. 60.
    Jarvis MF, Burgard EC, McGaraughty S, Honore P, Lynch K, Brennan TJ, Subieta A, Van Biesen T et al (2002) A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc Natl Acad Sci U S A 99(26):17179–17184.  https://doi.org/10.1073/pnas.252537299 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Seino D, Tokunaga A, Tachibana T, Yoshiya S, Dai Y, Obata K, Yamanaka H, Kobayashi K et al (2006) The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint. Pain 123(1–2):193–203.  https://doi.org/10.1016/j.pain.2006.02.032 PubMedCrossRefGoogle Scholar
  62. 62.
    Xu GY, Huang LY (2002) Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 22(1):93–102PubMedCrossRefGoogle Scholar
  63. 63.
    Jarvis MF (2003) Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain. Expert Opin Ther Targets 7(4):513–522.  https://doi.org/10.1517/14728222.7.4.513 PubMedCrossRefGoogle Scholar
  64. 64.
    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(12):4680–4685PubMedCrossRefGoogle Scholar
  65. 65.
    Reichling DB, Levine JD (2009) Critical role of nociceptor plasticity in chronic pain. Trends Neurosci 32(12):611–618.  https://doi.org/10.1016/j.tins.2009.07.007 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Cunha TM, Verri WA, Silva JS, Poole S, Cunha FQ, Ferreira SH (2005) A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci U S A 102(5):1755–1760.  https://doi.org/10.1073/pnas.0409225102 PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Aley KO, Martin A, McMahon T, Mok J, Levine JD, Messing RO (2001) Nociceptor sensitization by extracellular signal-regulated kinases. J Neurosci 21(17):6933–6939PubMedCrossRefGoogle Scholar
  68. 68.
    Coleman RA, Smith WL, Narumiya S (1994) International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 46(2):205–229PubMedGoogle Scholar
  69. 69.
    Ferreira SH, Nakamura M (1979) I - prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process. Prostaglandins 18(2):179–190PubMedCrossRefGoogle Scholar
  70. 70.
    Aley KO, Levine JD (1999) Role of protein kinase A in the maintenance of inflammatory pain. J Neurosci 19(6):2181–2186PubMedCrossRefGoogle Scholar
  71. 71.
    Kawabata A (2011) Prostaglandin E2 and pain--an update. Biol Pharm Bull 34(8):1170–1173PubMedCrossRefGoogle Scholar
  72. 72.
    Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA (2011) HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333(6048):1462–1466.  https://doi.org/10.1126/science.1206243 PubMedCrossRefGoogle Scholar
  73. 73.
    Hucho TB, Dina OA, Levine JD (2005) Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. J Neurosci 25(26):6119–6126.  https://doi.org/10.1523/JNEUROSCI.0285-05.2005 PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Larissa G. Pinto
    • 1
    • 2
  • Guilherme R. Souza
    • 1
  • Ricardo Kusuda
    • 1
  • Alexandre H. Lopes
    • 1
  • Morena B. Sant’Anna
    • 1
    • 3
  • Fernando Q. Cunha
    • 1
  • Sérgio H. Ferreira
    • 1
  • Thiago M. Cunha
    • 1
    Email author
  1. 1.Department of Pharmacology, Ribeirão Preto Medical SchoolUniversity of São PauloSão PauloBrazil
  2. 2.Wolfson Centre for Age-Related DiseasesKing’s College LondonLondonUK
  3. 3.Laboratory of Pain and SignalingButantan InstituteSão PauloBrazil

Personalised recommendations