title: Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat.
abstract: 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.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.forename: S M
authors.initials: SM
authors.lastname: Brown
authors.forename: H
authors.initials: H
authors.lastname: Ao
authors.forename: D H
authors.initials: DH
authors.lastname: Lee
authors.forename: E S
authors.initials: ES
authors.lastname: Higuera
authors.forename: A E
authors.initials: AE
authors.lastname: Dubin
authors.forename: S R
authors.initials: SR
authors.lastname: Chaplan
mesh_terms: D000208:Acute Disease; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D002908:Chronic Disease; D054815:Cyclic Nucleotide-Gated Cation Channels; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018862:Merkel Cells / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D012867:Skin / Q000294:innervation* / Q000503:physiopathology
chemical_list: D002317:Cardiovascular Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788