The role of HCN channels within the periaqueductal gray in neuropathic pain

Peripheral and spinal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a key role in neuropathic pain by regulating neuronal excitability. HCN channels are expressed in the ventral–lateral periaqueductal gray (vlPAG), a region that is important for pain modulation. However, the role of vlPAG HCN channels in neuropathic pain remains poorly understood. In the present study, we investigated the impact of changes to vlPAG HCN channels on neural activity in neuropathic pain. First, sciatic nerve chronic constriction injury (CCI) was established as a neuropathic pain model. Then, changes in HCN channels and their influence on vlPAG neuronal activity were detected. Our results indicate that after CCI surgery the following changes occur in vlPAG neurons: the expression of HCN1 and HCN2 channels is increased, the amplitude of the hyperpolarization-activated current (Ih) is augmented and its activation curve is shifted to more positive potentials and there is an increase in the frequency of action potential (AP) firing and spontaneous EPSCs that is attenuated by ZD7288, a HCN channel blocker. In addition, forskolin, which can elevate intracellular cAMP, mimics the CCI induced changes in neuronal excitability in the vlPAG. The effects of forskolin were also reversed by ZD7288. Taken together, the present data indicate an important role for HCN channels in the vlPAG in neuropathic pain.

► CCI surgery increased HCN channels expression and augmented Ih currents in vlPAG.
► Enhanced Ih currents contribute to increased neural excitability in vlPAG during pain.
► cAMP pathway involved in regulation of Ih currents on neuronal activity in vlPAG.