A Positive Allosteric Modulator of the Adenosine A1 Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model
A Positive Allosteric Modulator of the Adenosine A1 Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model
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DOI：
10.1124/mol.115.099499
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发表时间：
2015-09-01
影响因子：
3.6
通讯作者：
Christie, Macdonald J.
中科院分区：
文献类型：
--
作者：
Imlach, Wendy L.;Bhola, Rebecca F.;Christie, Macdonald J.
在脊髓和外周，腺苷通过激活腺苷A（1）受体（A1 R）抑制神经元活动，导致抗伤害感受，并突出了治疗靶向受体治疗神经性疼痛的潜力。本研究探讨了腺苷张力和A1 R信号的变化，以及一种新的A1 R正变构调节剂（PAM），VCP 171 [（2-氨基-4-（3-（三氟甲基）苯基）噻吩-3-基）（苯基）甲酮]，在大鼠部分神经损伤模型的神经病理性疼痛脊髓浅层背角突触兴奋性和抑制性神经传递的作用。在不存在A1 R激动剂的情况下，灌流A1 R拮抗剂8-环戊基-1，3-二丙基黄嘌呤（DPCPX; 1 μ M），在神经损伤动物的I和II层神经元中电诱发的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的突触电流（eEPSC）幅度比对照组显著增加，提示内源性腺苷张力在背角中增加。DPCPX还能显著增加对照组GABA能和甘氨酸能抑制性突触电流，但神经损伤后无差异。A1受体激动剂，N6-环戊基腺苷，产生更大的抑制eEPSC振幅在第二层，但不是第一层的脊髓背角神经损伤与对照组动物，这表明在第二层神经元的A1受体敏感性神经损伤后的功能增加。与对照动物相比，A1 R PAM（VCP 171）对I层和II层神经元的eEPSC神经损伤幅度产生了更大的抑制作用。神经损伤后背角兴奋性突触的腺苷张力和A1 R敏感性增强表明，A1 R的新一代PAM可以有效治疗神经病理性疼痛。
In the spinal cord and periphery, adenosine inhibits neuronal activity through activation of the adenosine A(1) receptor (A1R), resulting in antinociception and highlighting the potential of therapeutically targeting the receptor in the treatment of neuropathic pain. This study investigated the changes in adenosine tone and A1R signaling, together with the actions of a novel A1R positive allosteric modulator (PAM), VCP171 [(2-amino-4-(3-(trifluoromethyl) phenyl) thiophen-3-yl)(phenyl) methanone], on excitatory and inhibitory neurotransmission at spinal cord superficial dorsal horn synapses in a rat partial nerve-injury model of neuropathic pain. In the absence of A1R agonists, superfusion of the A1R antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 mu M), produced a significantly greater increase in electrically evoked alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor-mediated synaptic current (eEPSC) amplitude in both lamina I and II neurons from nerve-injured animals than in controls, suggesting that endogenous adenosine tone is increased in the dorsal horn. Inhibitory GABAergic and glycinergic synaptic currents were also significantly increased by DPCPX in controls but there was no difference after nerve injury. The A1R agonist, N6-cyclopentyladenosine, produced greater inhibition of eEPSC amplitude in lamina II but not lamina I of the spinal cord dorsal horn in nerve-injured versus control animals, suggesting a functional increase in A1R sensitivity in lamina II neurons after nerve injury. The A1R PAM, VCP171, produced a greater inhibition of eEPSC amplitude of nerve-injury versus control animals in both lamina I and lamina II neurons. Enhanced adenosine tone and A1R sensitivity at excitatory synapses in the dorsal horn after nerve injury suggest that new generation PAMs of the A1R can be effective treatments for neuropathic pain.