A hallmark of peripheral
neuropathic pain (PNP) is chronic spontaneous
pain and/or
hypersensitivity to normally painful stimuli (
hyperalgesia) or normally nonpainful stimuli (
allodynia).This
pain results partly from abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. We have previously shown, using a modified version of the lumbar 5 (L5)-spinal nerve
ligation model of PNP (mSNA model involving L5-spinal nerve
axotomy plus loose
ligation of the lumbar 4 (L4)-spinal nerve with
neuroinflammation-inducing chromic-gut), that L4 DRG neurons exhibit increased spontaneous activity, the key characteristic of neuronal hyperexcitability. The underlying ionic and molecular mechanisms of the hyperexcitability of L4 DRG neurons are incompletely understood, but could result from changes in expression and/or function of
ion channels including hyperpolarization-activated
cyclic nucleotide-gated (HCN) channels, which are active near the neuron's resting membrane potential, and which produce an excitatory inward current that depolarizes the membrane potential toward the threshold of action potential generation. Therefore, in the present study we used the mSNA model to investigate whether: (a) expression of HCN1-HCN3 channels is altered in L4 DRG neurons which, in the mSNA model, are essential for transmission of the evoked
pain, and which contribute to chronic spontaneous
pain, and (b) local (intraplantar) blockade of these HCN channels, with a specific blocker,
ZD7288, attenuates chronic spontaneous
pain and/or evoked
pain in mSNA rats. We found 7days after mSNA: (1) a significant increase in HCN2-immunoreactivity in small (<30μm) DRG neurons (predominantly IB4-negative neurons), and in the proportion of small neurons expressing HCN2 (putative nociceptors); (2) no significant change in HCN1- or HCN3-immunoreactivity in all cell types; and (3) attenuation, with
ZD7288 (100μM intraplantar), of chronic spontaneous
pain behavior (spontaneous foot lifting) and mechanical, but not, heat
hypersensitivity. The results suggest that peripheral HCN channels contribute to mechanisms of spinal nerve injury-induced PNP, and that HCN channels, possibly HCN2, represent a novel target for PNP treatment.