Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons

被引:41
|
作者
Coppi, Elisabetta [1 ]
Cherchi, Federica [1 ]
Fusco, Irene [1 ]
Failli, Paola [1 ]
Vona, Alessia [1 ]
Dettori, Ilaria [1 ]
Gaviano, Lisa [1 ]
Lucarini, Elena [1 ]
Jacobson, Kenneth A. [2 ]
Tosh, Dilip K. [2 ]
Salvemini, Daniela [3 ]
Ghelardini, Carla [1 ]
Pedata, Felicita [1 ]
Mannelli, Lorenzo Di Cesare [1 ]
Pugliese, Anna Maria [1 ]
机构
[1] Univ Florence, Dept NEUROFARBA, Div Pharmacol & Toxicol, Viale Pieraccini 6, I-50139 Florence, Italy
[2] NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA
[3] St Louis Univ, Sch Med, Dept Pharmacol & Physiol, St Louis, MO USA
关键词
Dorsal root ganglion neurons; Pronociceptive Ca2+ currents; Adenosine A(3) receptors; Action potential; INDUCED NEUROPATHIC PAIN; GATED CALCIUM-CHANNELS; MOUSE SENSORY NEURONS; INTRATHECAL ZICONOTIDE; RAT; AGONISTS; CONDUCTANCE; SUBUNIT; RELEASE;
D O I
10.1097/j.pain.0000000000001488
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Recently, studies have focused on the antihyperalgesic activity of the A(3) adenosine receptor (A(3)AR) in several chronic pain models, but the cellular and molecular basis of this effect is still unknown. Here, we investigated the expression and functional effects of A(3)AR on the excitability of small-to medium-sized, capsaicin-sensitive, dorsal root ganglion (DRG) neurons isolated from 3- to 4-week-old rats. Real-time quantitative polymerase chain reaction experiments and immunofluorescence analysis revealed A(3)AR expression in DRG neurons. Patch-clamp experiments demonstrated that 2 distinct A(3)AR agonists, Cl-IB-MECA and the highly selective MRS5980, inhibited Ca2+-activated K+ (K-Ca) currents evoked by a voltage-ramp protocol. This effect was dependent on a reduction in Ca2+ influx via N-type voltage-dependent Ca2+ channels, as Cl-IB-MECA-induced inhibition was sensitive to the N-type blocker PD173212 but not to the L-type blocker, lacidipine. The endogenous agonist adenosine also reduced N-type Ca2+ currents, and its effect was inhibited by 56% in the presence of A(3)AR antagonist MRS1523, demonstrating that the majority of adenosine's effect is mediated by this receptor subtype. Current-clamp recordings demonstrated that neuronal firing of rat DRG neurons was also significantly reduced by A(3)AR activation in a MRS1523-sensitive but PD173212-insensitive manner. Intracellular Ca2+ measurements confirmed the inhibitory role of A(3)AR on DRG neuronal firing. We conclude that pain-relieving effects observed on A(3)AR activation could be mediated through N-type Ca2+ channel block and action potential inhibition as independent mechanisms in isolated rat DRG neurons. These findings support A(3)AR-based therapy as a viable approach to alleviate pain in different pathologies.
引用
收藏
页码:1103 / 1118
页数:16
相关论文
共 16 条
  • [1] Covalently Binding Adenosine A3 Receptor Agonist ICBM Irreversibly Reduces Voltage-Gated Ca2+ Currents in Dorsal Root Ganglion Neurons
    Cherchi, Federica
    Venturini, Martina
    Magni, Giada
    Scortichini, Mirko
    Jacobson, Kenneth A.
    Pugliese, Anna Maria
    Coppi, Elisabetta
    PURINERGIC SIGNALLING, 2024, 20 (01) : 35 - 45
  • [2] Oral Communication: Adenosine A3 receptor stimulation inhibits pro-nociceptive voltage-dependent Ca2+ currents in rat dorsal root ganglion neurons
    Coppi, Elisabetta
    PURINERGIC SIGNALLING, 2018, 14 : S32 - S33
  • [3] Covalently Binding Adenosine A3 Receptor Agonist ICBM Irreversibly Reduces Voltage-Gated Ca2+ Currents in Dorsal Root Ganglion Neurons
    Federica Cherchi
    Martina Venturini
    Giada Magni
    Mirko Scortichini
    Kenneth A. Jacobson
    Anna Maria Pugliese
    Elisabetta Coppi
    Purinergic Signalling, 2024, 20 : 35 - 45
  • [4] Protease-Activated Receptor 2 Activation Inhibits N-Type Ca2+ Currents in Rat Peripheral Sympathetic Neurons
    Kim, Young-Hwan
    Ahn, Duck-Sun
    Kim, Myeong Ok
    Joeng, Ji-Hyun
    Chung, Seungsoo
    MOLECULES AND CELLS, 2014, 37 (11) : 804 - 811
  • [5] Neuromedin U inhibits T-type Ca2+ channel currents and decreases membrane excitability in small dorsal root ganglia neurons in mice
    Wang, Fen
    Zhang, Yuan
    Jiang, Xinghong
    Zhang, Yiming
    Zhang, Ling
    Gong, Shan
    Liu, Chunfeng
    Zhou, Ligang
    Tao, Jin
    CELL CALCIUM, 2011, 49 (01) : 12 - 22
  • [6] Propofol inhibits expression of angiotensin II receptor type 2 in dorsal root ganglion neurons
    Pan, Bingbing
    Cheng, Zhigang
    Kong, Gaoyin
    Song, Zongbin
    Wang, Yunjiao
    Wei, Lai
    Xiao, Dan
    Zhao, Yuan
    Guo, Qulian
    EXPERIMENTAL AND THERAPEUTIC MEDICINE, 2017, 13 (03) : 867 - 872
  • [7] T-type Ca2+ channels play a dual role in modulating the excitability of dorsal root ganglia neurons
    Zhu, Tong
    Wang, Yuying
    MOLECULAR PAIN, 2022, 18
  • [8] Activation of M3 muscarinic receptors inhibits T-type Ca2+ channel currents via pertussis toxin-sensitive novel protein kinase C pathway in small dorsal root ganglion neurons
    Zhang, Yiming
    Zhang, Ling
    Wang, Fen
    Zhang, Yi
    Wang, Jiangong
    Qin, Zhenghong
    Jiang, Xinghong
    Tao, Jin
    CELLULAR SIGNALLING, 2011, 23 (06) : 1057 - 1067
  • [9] 5-HT3 Receptors in Rat Dorsal Root Ganglion Neurons: Ca2+ Entry and Modulation of Neurotransmitter Release
    Martinello, Katiuscia
    Sucapane, Antonietta
    Fucile, Sergio
    LIFE-BASEL, 2022, 12 (08):
  • [10] Regulation of L- and N-types of Ca2+ channels by intracellular ATP4- in frog dorsal root ganglion neurons
    Yuki, T
    Yamaoka, K
    Seyama, I
    PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1999, 438 (02): : 117 - 124