RT Journal Article
SR Electronic
T1 Prostanoid EP4 Receptor-Mediated Augmentation of <em>I</em><sub>h</sub> Currents in A<em>β</em> Dorsal Root Ganglion Neurons Underlies Neuropathic Pain
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 50
OP 58
DO 10.1124/jpet.118.252767
VO 368
IS 1
A1 Hao Zhang
A1 Toshihide Kashihara
A1 Tsutomu Nakada
A1 Satoshi Tanaka
A1 Kumiko Ishida
A1 Satoshi Fuseya
A1 Hiroyuki Kawagishi
A1 Kenkichi Kiyosawa
A1 Mikito Kawamata
A1 Mitsuhiko Yamada
YR 2019
UL http://jpet.aspetjournals.org/content/368/1/50.abstract
AB An injury of the somatosensory system causes neuropathic pain, which is usually refractory to conventional analgesics, thus warranting the development of novel drugs against this kind of pain. The mechanism of neuropathic pain in rats that had undergone left L5 spinal nerve transection was analyzed. Ten days after surgery, these rats acquired neuropathic pain. The patch-clamp technique was used on the isolated bilateral L5 dorsal root ganglion neurons. The current-clamped neurons on the ipsilateral side exhibited significantly higher excitability than those on the contralateral side. However, only neurons with diameters of 40–50 μm on the ipsilateral side exhibited significantly larger voltage sags in response to hyperpolarizing current pulses than those on the contralateral side. Under the voltage clamp, only these neurons on the ipsilateral side showed a significantly larger density of an inward current at &lt; −80 mV [hyperpolarization-activated nonselective cation (Ih) current] with a rightward-shifted activation curve than that on the contralateral side. Ivabradine—an Ih current inhibitor—inhibited Ih currents in these neurons on both sides in a similar concentration-dependent manner, with an IC50 value of ∼3 μM. Moreover, the oral administration of ivabradine significantly alleviated the neuropathic pain on the ipsilateral side. An inhibitor of adenylyl cyclase or an antagonist of prostanoid EP4 receptors (CJ-023423) inhibited ipsilateral, but not contralateral Ih, currents in these neurons. Furthermore, the intrathecal administration of CJ-023423 significantly attenuated neuropathic pain on the ipsilateral side. Thus, ivabradine and/or CJ-023423 may be a lead compound for the development of novel therapeutics against neuropathic pain.