Hyperpolarization-activated,
cyclic nucleotide-modulated (HCN) channels contribute to rhythmic spontaneous activity in the heart and CNS. Ectopic spontaneous neuronal activity has been implicated in the development and maintenance of acute and chronic
hyperalgesia,
allodynia and spontaneous
pain. Previously, we documented that systemic administration of
ZD7288, a specific blocker of pacemaker current (I(h)), decreased ectopic activity in dorsal root ganglion (DRG) and reversed
tactile allodynia in spinal nerve ligated (SNL) rats [Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM, Dubin AE (2003) Neuronal hyperpolarization-activated pacemaker channels drive
neuropathic pain. J Neurosci 23:1169-1178]. Spontaneous
pain is the chief clinical manifestation of
peripheral nerve injury; however, a role for I(h) in spontaneous
pain has not been described. Here, in further rat studies, we report that systemic administration of
ZD7288 reversed spontaneous
pain induced by mild thermal injury (MTI) and
tactile allodynia induced by SNL and MTI. In contrast,
ZD7288 did not reduce
thermal hyperalgesia. An important locus of action appears to be in the skin since intraplantar (local) administration of
ZD7288 completely suppressed
tactile allodynia arising from MTI and SNL and reduced spontaneous
pain due to MTI. Immunohistochemical staining of plantar skin sections detected HCN1-HCN4 expression in mechanosensory structures (e.g., Meissner's corpuscles and Merkel cells). Collectively, these data suggest that expression and modulation of I(h) in the peripheral nervous system, including specialized sensory structures, may play a significant role in sensory processing and contribute to spontaneous
pain and
tactile allodynia.