Prostanoid EP4 Receptor-Mediated Augmentation of I_h Currents in Aβ Dorsal Root Ganglion Neurons Underlies Neuropathic Pain

Abstract

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 mm 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 , 280 mV [hyperpolarization-activated nonselective cation (I h) current] with a rightward-shifted activation curve than that on the contralateral side. Ivabradine-an I h current inhibitor-inhibited I h currents in these neurons on both sides in a similar concentrationdependent manner, with an IC 50 value of ∼3 mM. 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 I h , 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.

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

“…A recent study showed that decreased function of inhibitory interneurons in the spinal dorsal horn of rodents with peripheral nerve injury is involved in conversion from non-painful to painful sensation 28 . The results of the present study are in line with the results of our previous study showing that oral administration of ivabradine alleviated mechanical allodynia in rats with neuropathic pain via inhibition of the HCN current in Aβ DRG neurons 11 . It is presumed that reduction of the area of dynamic mechanical allodynia observed in the present study is due to the inhibition of HCN channels in low-threshold mechanoreceptor neurons in the DRG.…”

“…Analgesic effects of some clinically available drugs for neuropathic pain such as pregabalin 26 and amitriptyline 27 become evident in patients after the second day of oral administration. Similarly, cumulative effects of oral ivabradine on mechanical allodynia (maximal effects being observed after 2–4 days) were reported in animal models with neuropathic pain 9 , 11 , indicating the possibility that repeated administration of ivabradine can produce stable concentrations of ivabradine and that suppression of HCN channels for a certain period of time is required to achieve an anti-allodynic effect. Non-noxious mechanical information is conveyed to the spinal dorsal horn mainly via low-threshold mechanoreceptors (Aβ-fibers) 19 , 20 but is pathologically converted to pain in the setting of neuropathic pain.…”

“…Ivabradine reduced pain behavior in the second phase (inflammatory) in a formalin model but had no effect in the early nociceptive phase 10 . It is important to note that our laboratory 11 and Noh et al . 9 have shown that the first dose of oral administration of ivabradine did not clearly have an anti-allodynic effect, but the anti-allodynic effects became evident after the second day of repeated oral administration in rodents with neuropathic pain.…”

“…Ivabradine can reduce the resting heart rate mainly through blockade of HCN4 channels with few serious side effects 3 , 5 . In addition, it has been reported that ivabradine alleviates neuropathic pain 9 – 11 and inflammatory pain 10 , 12 in rodent models. Ivabradine reduced pain behavior in the second phase (inflammatory) in a formalin model but had no effect in the early nociceptive phase 10 .…”

“…Dynamic mechanical allodynia in the secondary zone is mediated mainly by low-threshold mechanoreceptors (Aβ-fibers) 19 , 20 . Our previous study showed that oral administration of ivabradine alleviates mechanical allodynia in rats with neuropathic pain via inhibition of the HCN current in large DRG neurons 11 , which are considered to be Aβ-fibers 21 .…”