Background Sympathetically maintained pain (SMP) involves an increased excitability of dorsal root ganglion (DRG) neurons to sympathetic nerve stimulation and circulating norepinephrine. The current treatment of SMP has limited efficacy, and hence more mechanistic insights into this intractable pain condition are urgently needed.
Methods A caudal trunk transection (CTT) model of neuropathic pain was established in mice.
Immunofluorescence staining, small interfering RNA, pharmacological and electrophysiological studies were conducted to test the hypothesis that norepinephrine increases the excitability of small-diameter DRG neurons from CTT mice through the activation of cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway.
Results Behavior study showed that CTT mice developed mechanical and heat hypersensitivities, which were attenuated by intraperitoneal injection of guanethidine. CTT mice also showed an abnormal sprouting of tyrosine hydroxylase-positive nerve fibers in DRG, and an increased excitability of small-diameter DRG neurons to norepinephrine, suggesting that CTT is a useful model to study SMP. Importantly, inhibiting cGMP-PKG pathway with small interfering RNA and KT5823 attenuated the increased sympathetic sensitivity in CTT mice. In contrast, cGMP activators (Sp-cGMP, 8-Br-cGMP) further increased sympathetic sensitivity. Furthermore, phosphorylation of ATP-sensitive potassium channel, which is a downstream target of PKG, may contribute to the adrenergic modulation of DRG neuron excitability.
Conclusions Our findings suggest an important role of cGMP-PKG signaling pathway in the increased excitability of small-diameter DRG neurons to norepinephrine after CTT, which involves an inhibition of the ATP-sensitive potassium currents through PKG-induced phosphorylation. Accordingly, drugs targeting this pathway may help to treat SMP.
- pain perception
- chronic pain
- complex regional pain syndromes
- animal experimentation
Data availability statement
Data are available on reasonable request.
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HL, MS and LL contributed equally.
Contributors JX and HL conceived the experiment; HL, MS, LL, XL, JH and QH collected the data; HL, LL and QH analyzed the data; JX, HL and MS wrote the paper.
Funding This work was supported by a grant from the National Natural Science Foundation of China (31671089).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.