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Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons

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Abstract

Objective and design

Our aim was to determine an age-dependent role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in a rat pre-clinical model of long-term inflammatory pain.

Methods

We compared 6 and 24 months-old female Wistar rats after cutaneous inflammation. We used behavioral pain assessments over time, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA and in vitro treatment with cytokines.

Results

Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1β up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1β had this effect only on young and aged neurons, respectively.

Conclusion

Inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

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Data availability

The data that support the findings of this study are available from authors upon reasonable request.

References

  1. Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain. 2006;7(5 Suppl 3):S1-29.

    Article  CAS  PubMed  Google Scholar 

  2. Stemkowski PL, Smith PA. Sensory neurons, ion channels, inflammation and the onset of neuropathic pain. Can J Neurol Sci. 2012;39(4):416–35.

    Article  PubMed  Google Scholar 

  3. Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014;13(7):533–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ghlichloo I, Gerriets V. Nonsteroidal anti-inflammatory drugs (NSAIDs). 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 31613522.

  6. Reid MC, Eccleston C, Pillemer K. Management of chronic pain in older adults. BMJ. 2015;350:h532.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90.

    Article  CAS  PubMed  Google Scholar 

  8. Messina DN, Peralta ED, Seltzer AM, Patterson SI, Acosta CG. Age-dependent and modality-specific changes in the phenotypic markers Nav1.8, ASIC3, P2X3 and TRPM8 in male rat primary sensory neurons during healthy aging. Biogerontology. 2023;24(1):111–36.

    Article  CAS  PubMed  Google Scholar 

  9. Fang X, Djouhri L, McMullan S, Berry C, Okuse K, Waxman SG, Lawson SN. trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors. J Neurosci. 2005;25(19):4868–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hameed S. Na(v)1.7 and Na(v)1.8: Role in the pathophysiology of pain. Mol Pain. 2019;15:1744806919858801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 2004;108(3):237–47.

    Article  CAS  PubMed  Google Scholar 

  12. Gold MS, Reichling DB, Shuster MJ, Levine JD. Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci U S A. 1996;93(3):1108–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cummins TR, Black JA, Dib-Hajj SD, Waxman SG. Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons. J Neurosci. 2000;20(23):8754–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fjell J, Cummins TR, Dib-Hajj SD, Fried K, Black JA, Waxman SG. Differential role of GDNF and NGF in the maintenance of two TTX-resistant sodium channels in adult DRG neurons. Brain ResMolBrain Res. 1999;67(2):267–82.

    Article  CAS  Google Scholar 

  15. Kerr BJ, Souslova V, McMahon SB, Wood JN. A role for the TTX-resistant sodium channel Nav 18 in NGF-induced hyperalgesia, but not neuropathic pain. NeuroReport. 2001;12(14):3077–80.

    Article  CAS  PubMed  Google Scholar 

  16. Waldmann R, Champigny G, Lingueglia E, De Weille JR, Heurteaux C, Lazdunski M. H(+)-gated cation channels. Ann N Y Acad Sci. 1999;868:67–76.

    Article  CAS  PubMed  Google Scholar 

  17. Deval E, Noel J, Lay N, Alloui A, Diochot S, Friend V, Jodar M, Lazdunski M, Lingueglia E. ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J. 2008;27(22):3047–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Steingrimsdottir OA, Landmark T, Macfarlane GJ, Nielsen CS. Defining chronic pain in epidemiological studies: a systematic review and meta-analysis. Pain. 2017;158(11):2092–107.

    Article  PubMed  Google Scholar 

  19. Becker JB, Prendergast BJ, Liang JW. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol Sex Differ. 2016;7:34.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Levy DR, Hunter N, Lin S, Robinson EM, Gillis W, Conlin EB, Anyoha R, Shansky RM, Datta SR. Mouse spontaneous behavior reflects individual variation rather than estrous state. Curr Biol. 2023;33:1358.

    Article  CAS  PubMed  Google Scholar 

  21. Shansky RM, Murphy AZ. Considering sex as a biological variable will require a global shift in science culture. Nat Neurosci. 2021;24(4):457–64.

    Article  CAS  PubMed  Google Scholar 

  22. Benitez SG, Seltzer AM, Messina DN, Foscolo MR, Patterson SI, Acosta CG. Cutaneous inflammation differentially regulates the expression and function of angiotensin-II types 1 and 2 receptors in rat primary sensory neurons. J Neurochem. 2020;152(6):675–96.

    Article  CAS  PubMed  Google Scholar 

  23. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55–63.

    Article  CAS  PubMed  Google Scholar 

  24. Choi Y, Yoon YW, Na HS, Kim SH, Chung JM. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain. 1994;59(3):369–76.

    Article  Google Scholar 

  25. Xing H, Chen M, Ling J, Tan W, Gu JG. TRPM8 mechanism of cold allodynia after chronic nerve injury. J Neurosci. 2007;27(50):13680–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Marsh B, Acosta C, Djouhri L, Lawson SN. Leak K(+) channel mRNAs in dorsal root ganglia: relation to inflammation and spontaneous pain behaviour. MolCell Neurosci. 2012;49(3):375–86.

    CAS  Google Scholar 

  27. Schoor O, Weinschenk T, Hennenlotter J, Corvin S, Stenzl A, Rammensee HG, Stevanovic S. Moderate degradation does not preclude microarray analysis of small amounts of RNA. Biotechniques. 2003;35(6):1192–6.

    Article  CAS  PubMed  Google Scholar 

  28. Bustin SA. Why the need for qPCR publication guidelines?—The case for MIQE. Methods. 2010;50(4):217–26.

    Article  CAS  PubMed  Google Scholar 

  29. Siqueira SR, Alves B, Malpartida HM, Teixeira MJ, Siqueira JT. Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience. 2009;164(2):573–7.

    Article  CAS  PubMed  Google Scholar 

  30. Deval E, Noel J, Gasull X, Delaunay A, Alloui A, Friend V, Eschalier A, Lazdunski M, Lingueglia E. Acid-sensing ion channels in postoperative pain. J Neurosci. 2011;31(16):6059–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Giulietti A, Overbergh L, Valckx D, Decallonne B, Bouillon R, Mathieu C. An overview of real-time quantitative PCR: applications to quantify cytokine gene expression. Methods. 2001;25(4):386–401.

    Article  CAS  PubMed  Google Scholar 

  32. Molliver DC, Lindsay J, Albers KM, Davis BM. Overexpression of NGF or GDNF alters transcriptional plasticity evoked by inflammation. Pain. 2005;113(3):277–84.

    Article  CAS  PubMed  Google Scholar 

  33. Pezet S, Krzyzanowska A, Wong LF, Grist J, Mazarakis ND, Georgievska B, McMahon SB. Reversal of neurochemical changes and pain-related behavior in a model of neuropathic pain using modified lentiviral vectors expressing GDNF. Mol Ther. 2006;13(6):1101–9.

    Article  CAS  PubMed  Google Scholar 

  34. Acosta C, Djouhri L, Watkins R, Berry C, Bromage K, Lawson SN. TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain. JNeurosci. 2014;34(4):1494–509.

    Article  CAS  Google Scholar 

  35. Messina DN, Peralta ED, Acosta CG. Glial-derived neurotrophic factor regulates the expression of TREK2 in rat primary sensory neurons leading to attenuation of axotomy-induced neuropathic pain. Exp Neurol. 2022;357:114190.

    Article  CAS  PubMed  Google Scholar 

  36. Lawson SN. Phenotype and function of somatic primary afferent nociceptive neurones with C-Adelta- or Aalpha/beta-fibres. ExpPhysiol. 2002;87(2):239–44.

    Google Scholar 

  37. Fang X, Djouhri L, McMullan S, Berry C, Waxman SG, Okuse K, Lawson SN. Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression. J Neurosci. 2006;26(27):7281–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gao LL, McMullan S, Djouhri L, Acosta C, Harper AA, Lawson SN. Expression and properties of hyperpolarization-activated current in rat dorsal root ganglion neurons with known sensory function. J Physiol. 2012;590(19):4691–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Haskins W, Benitez S, Mercado JM, Acosta CG. Cutaneous inflammation regulates THIK1 expression in small C-like nociceptor dorsal root ganglion neurons. Mol Cell Neurosci. 2017;83:13–26.

    Article  CAS  PubMed  Google Scholar 

  40. Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong C, Mikusa JP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I, Gregg R, Matulenko M, Hakeem A, Gross M, Johnson M, Marsh K, Wagoner PK, Sullivan JP, Faltynek CR, Krafte DS. A-803467, a potent and selective Nav18 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci U S A. 2007;104(20):8520–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huang X, Jin X, Huang G, Huang J, Wu T, Li Z, Chen J, Kong F, Pan X, Yan N. Structural basis for high-voltage activation and subtype-specific inhibition of human Na(v)18. Proc Natl Acad Sci U S A. 2022;119(30):2208211119.

    Article  Google Scholar 

  42. McGaraughty S, Chu KL, Scanio MJ, Kort ME, Faltynek CR, Jarvis MF. A selective Nav18 sodium channel blocker, A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats. J Pharmacol Exp Ther. 2008;324(3):1204–11.

    Article  CAS  PubMed  Google Scholar 

  43. Karczewski J, Spencer RH, Garsky VM, Liang A, Leitl MD, Cato MJ, Cook SP, Kane S, Urban MO. Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2. Br J Pharmacol. 2010;161(4):950–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Robson LG, Dyall SC, Sidloff D, Michael-Titus AT. Omega-3 polyunsaturated fatty acids increase the neurite outgrowth of rat sensory neurones throughout development and in aged animals. Neurobiol Aging. 2010;31(4):678–87.

    Article  CAS  PubMed  Google Scholar 

  45. Rafiyan M, Sadeghmousavi S, Akbarzadeh M, Rezaei N. Experimental animal models of chronic inflammation. Curr Res Immunol. 2023;4:100063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Blanchard MG, Rash LD, Kellenberger S. Inhibition of voltage-gated Na(+) currents in sensory neurones by the sea anemone toxin APETx2. Br J Pharmacol. 2012;165(7):2167–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Verkest C, Salinas M, Diochot S, Deval E, Lingueglia E, Baron A. Mechanisms of action of the peptide toxins targeting human and rodent acid-sensing ion channels and relevance to their in vivo analgesic effects. Toxins (Basel). 2022;14(10):709.

    Article  CAS  PubMed  Google Scholar 

  48. Almarestani L, Fitzcharles MA, Bennett GJ, Ribeiro-da-Silva A. Imaging studies in Freund’s complete adjuvant model of regional polyarthritis, a model suitable for the study of pain mechanisms, in the rat. Arthritis Rheum. 2011;63(6):1573–81.

    Article  PubMed  Google Scholar 

  49. Ferdousi MI, Calcagno P, Sanchez C, Smith KL, Kelly JP, Roche M, Finn DP. Characterization of pain-, anxiety-, and cognition-related behaviors in the complete Freund’s adjuvant model of chronic inflammatory pain in Wistar-Kyoto rats. Front Pain Res (Lausanne). 2023;4:1131069.

    Article  PubMed  Google Scholar 

  50. Martin KK, Parvin S, Garraway SM. Peripheral inflammation accelerates the onset of mechanical hypersensitivity after spinal cord injury and engages tumor necrosis factor alpha signaling mechanisms. J Neurotrauma. 2019;36(12):2000–10.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sendama W. The effect of ageing on the resolution of inflammation. Ageing Res Rev. 2020;57:101000.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Noh ASM, Chuan TD, Khir NAM, Zin AAM, Ghazali AK, Long I, Ab Aziz CB, Ismail CAN. Effects of different doses of complete Freund’s adjuvant on nociceptive behaviour and inflammatory parameters in polyarthritic rat model mimicking rheumatoid arthritis. PLoS ONE. 2021;16(12):e0260423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Morgan D, Mitzelfelt JD, Koerper LM, Carter CS. Effects of morphine on thermal sensitivity in adult and aged rats. J Gerontol A Biol Sci Med Sci. 2012;67(7):705–13.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Thapa D, Barrett B, Argunhan F, Brain SD. Influence of cold-TRP receptors on cold-influenced behaviour. Pharmaceuticals (Basel). 2021;15(1):42.

    Article  PubMed  Google Scholar 

  55. Kabadi R, Kouya F, Cohen HW, Banik RK. Spontaneous pain-like behaviors are more sensitive to morphine and buprenorphine than mechanically evoked behaviors in a rat model of acute postoperative pain. Anesth Analg. 2015;120(2):472–8.

    Article  CAS  PubMed  Google Scholar 

  56. Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, Gierthmuhlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihofner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Uceyler N, Valet M, Wasner G, Treede DR. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010;150(3):439–50.

    Article  CAS  PubMed  Google Scholar 

  57. Ma L, Liu S, Yi M, Wan Y. Spontaneous pain as a challenge of research and management in chronic pain. Med Rev. 2022;2(3):308–19.

    Article  Google Scholar 

  58. Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS. Changes in the expression of NaV17, NaV18 and NaV19 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain. 2008;12(5):564–72.

    Article  CAS  PubMed  Google Scholar 

  59. Ikeuchi M, Kolker SJ, Burnes LA, Walder RY, Sluka KA. Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. Pain. 2008;137(3):662–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Izumi M, Ikeuchi M, Ji Q, Tani T. Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis. J Biomed Sci. 2012;19(1):77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron. 2001;32(6):1071–83.

    Article  CAS  PubMed  Google Scholar 

  62. Zhou RP, Wu XS, Wang ZS, Xie YY, Ge JF, Chen FH. Novel insights into acid-sensing ion channels: implications for degenerative diseases. Aging Dis. 2016;7(4):491–501.

    Article  PubMed  Google Scholar 

  63. Chen WH, Hsieh CL, Huang CP, Lin TJ, Tzen JT, Ho TY, Lin YW. Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain. J Biomed Sci. 2011;18(1):82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Voilley N, de Weille J, Mamet J, Lazdunski M. Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci. 2001;21(20):8026–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Walder RY, Rasmussen LA, Rainier JD, Light AR, Wemmie JA, Sluka KA. ASIC1 and ASIC3 play different roles in the development of Hyperalgesia after inflammatory muscle injury. J Pain. 2010;11(3):210–8.

    Article  CAS  PubMed  Google Scholar 

  66. Ding J, Zhang R, Li H, Ji Q, Cheng X, Thorne RF, Hondermarck H, Liu X, Shen C. ASIC1 and ASIC3 mediate cellular senescence of human nucleus pulposus mesenchymal stem cells during intervertebral disc degeneration. Aging (Albany NY). 2021;13(7):10703–23.

    Article  CAS  PubMed  Google Scholar 

  67. Dulai JS, Smith ESJ, Rahman T. Acid-sensing ion channel 3: an analgesic target. Channels (Austin). 2021;15(1):94–127.

    Article  PubMed  Google Scholar 

  68. Morgan M, Thai J, Trinh P, Habib M, Effendi KN, Ivanusic JJ. ASIC3 inhibition modulates inflammation-induced changes in the activity and sensitivity of Adelta and C fiber sensory neurons that innervate bone. Mol Pain. 2020;16:1744806920975950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Atmaramani RR, Black BJ, de la Pena JB, Campbell ZT, Pancrazio JJ. Conserved Expression of Nav1.7 and Nav1.8 contribute to the spontaneous and thermally evoked excitability in IL-6 and NGF-sensitized adult dorsal root ganglion neurons in vitro. Bioengineering (Basel). 2020;7(2):44.

    Article  CAS  PubMed  Google Scholar 

  70. Kung CC, Huang YC, Hung TY, Teng CY, Lee TY, Sun WH. Deletion of acid-sensing ion channel 3 relieves the late phase of neuropathic pain by preventing neuron degeneration and promoting neuron repair. Cells. 2020;9(11):2355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee JYP, Saez NJ, Cristofori-Armstrong B, Anangi R, King GF, Smith MT, Rash LD. Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain. Br J Pharmacol. 2018;175(12):2204–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature. 2007;447(7146):855–8.

    Article  CAS  PubMed  Google Scholar 

  73. Luiz AP, MacDonald DI, Santana-Varela S, Millet Q, Sikandar S, Wood JN, Emery EC. Cold sensing by Na(V)18-positive and Na(V)18-negative sensory neurons. Proc Natl Acad Sci U S A. 2019;116(9):3811–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Askwith CC, Benson CJ, Welsh MJ, Snyder PM. DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature. Proc Natl Acad Sci U S A. 2001;98(11):6459–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, Nassar MA, Dickenson AH, Wood JN. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science. 2008;321(5889):702–5.

    Article  CAS  PubMed  Google Scholar 

  76. Roza C, Laird JM, Souslova V, Wood JN, Cervero F. The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol. 2003;550(Pt 3):921–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kleggetveit IP, Namer B, Schmidt R, Helas T, Ruckel M, Orstavik K, Schmelz M, Jorum E. High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain. 2012;153(10):2040–7.

    Article  CAS  PubMed  Google Scholar 

  78. Lee CH, Chen CC. Roles of ASICs in nociception and proprioception. Adv Exp Med Biol. 2018;1099:37–47.

    Article  CAS  PubMed  Google Scholar 

  79. DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001;90(1–2):1–6.

    Article  CAS  PubMed  Google Scholar 

  80. Zhang T, Zhang N, Zhang R, Zhao W, Chen Y, Wang Z, Xu B, Zhang M, Shi X, Zhang Q, Guo Y, Xiao J, Chen D, Fang Q. Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines. J Neuroinflammation. 2018;15(1):320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cook AD, Christensen AD, Tewari D, McMahon SB, Hamilton JA. Immune cytokines and their receptors in inflammatory pain. Trends Immunol. 2018;39(3):240–55.

    Article  CAS  PubMed  Google Scholar 

  82. Matsuda M, Huh Y, Ji RR. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J Anesth. 2019;33(1):131–9.

    Article  PubMed  Google Scholar 

  83. Ngwainmbi J, De DD, Smith TH, El-Hage N, Fitting S, Kang M, Dewey WL, Hauser KF, Akbarali HI. Effects of HIV-1 Tat on enteric neuropathogenesis. J Neurosci. 2014;34(43):14243–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chen X, Pang RP, Shen KF, Zimmermann M, Xin WJ, Li YY, Liu XG. TNF-alpha enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury. Exp Neurol. 2011;227(2):279–86.

    Article  CAS  PubMed  Google Scholar 

  85. Gong W, Kolker SJ, Usachev Y, Walder RY, Boyle DL, Firestein GS, Sluka KA. Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium. Arthritis Res Ther. 2014;16(3):R121.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Ross JL, Queme LF, Cohen ER, Green KJ, Lu P, Shank AT, An S, Hudgins RC, Jankowski MP. Muscle IL1beta drives ischemic myalgia via ASIC3-mediated sensory neuron sensitization. J Neurosci. 2016;36(26):6857–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhou R, Wu X, Wang Z, Ge J, Chen F. Interleukin-6 enhances acid-induced apoptosis via upregulating acid-sensing ion channel 1a expression and function in rat articular chondrocytes. Int Immunopharmacol. 2015;29(2):748–60.

    Article  CAS  PubMed  Google Scholar 

  88. de Magalhaes SF, Manzo LP, de Faria FM, de Oliveira-Fusaro MC, Nishijima CM, Vieira WF, Bonet IJM, Dos Santos GG, Tambeli CH, Parada CA. Inflammatory pain in peripheral tissue depends on the activation of the TNF-alpha type 1 receptor in the primary afferent neuron. Eur J Neurosci. 2021;53(2):376–89.

    Article  PubMed  Google Scholar 

  89. Wei S, Qiu CY, Jin Y, Liu TT, Hu WP. TNF-alpha acutely enhances acid-sensing ion channel currents in rat dorsal root ganglion neurons via a p38 MAPK pathway. J Neuroinflammation. 2021;18(1):92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

DNM and EDP: were supported by doctoral fellowships from the National Research Council of Argentina (CONICET). CGA is a Staff Scientist of the same organization. This work was funded by Fondo Nacional para la Ciencia y la Tecnología (FONCyT-ANPCyT PICT-2019-02666 to CGA), Proyecto de Financiamiento de Unidades Ejecutoras (PUE-2017-0025 to CGA) and by the Proyectos de Investigación Plurianual 2021–2023 (PIP-2230 to CGA). The sponsors of this research were not involved in the experimental design, writing of the manuscript or the decision to submit it. We thank Sean Patterson (IHEM-CONICET) for critical reading and editing of the manuscript.

Funding

Consejo Nacional de Investigaciones Científicas y Técnicas, Studentships, Studentships, CIC, Permanent Staff

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  1. Laboratory of Neurobiology of Pain, Faculty of Medical Sciences, IHEM (Instituto de Histologia y Embriologia Mendoza, Dr. Mario H Burgos), Cuyo National University, Av. Del Libertador 80, 5500, Mendoza, Argentina

    Diego N. Messina, Emanuel D. Peralta & Cristian G. Acosta

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  1. Diego N. Messina
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  2. Emanuel D. Peralta
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  3. Cristian G. Acosta
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Conceptualization: D.N.M & C.G.A.; Methodology: D.N.M., E.D.P. & C.G.A.; Formal analysis and investigation: D.N.M., E.D.P. & C.G.A.; Writing—original draft preparation: D.N.M. & C.G.A.; Writing—review and editing: D.N.M., E.D.P. & C.G.A.; Funding acquisition: C.G.A.; Supervision: C.G.A.

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Correspondence to Cristian G. Acosta.

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Messina, D.N., Peralta, E.D. & Acosta, C.G. Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons. Inflamm. Res. 73, 669–691 (2024). https://doi.org/10.1007/s00011-024-01862-z

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