KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

Abstract

BackgroundDiabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study.MethodsThe mRNA levels of KCNQ2/3/5 channels were analyzed by real-time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively.ResultsThe mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats.ConclusionThe findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.

Activation of Kv7 channels with the anticonvulsant retigabine alleviates neuropathic pain behaviour in the streptozotocin rat model of diabetic neuropathy

“…Our findings that retigabine reduced mechanical hypersensitivity in STZ-diabetic are in line with these findings. In contrast, however, our results show that retigabine given at higher doses (15 mg/kg and 7.5 mg/kg) than that (5 mg/kg) used by these investigators [60] had no effect on heat hypersensitivity in STZ-diabetic rats. The reason for this apparent discrepancy might be due to a difference in the rat strain (Sprague Dawley in the present study versus Wistar in their study).…”

“…Indeed, retigabine has been shown to display analgesic efficacy in multiple animal pain models including models of temporomandibular joint pain [52], visceral pain [53], inflammatory and nerve injury-induced PNP [16,44,54,55], spinal cord injury [56]; trigeminal neuropathy [57], bone cancer pain [58] and chemotherapy-induced PNP [59]. However, as far as we know, there has been only one study showing that retigabine attenuated both mechanical and heat hypersensitivity in STZ rats [60]. Our findings that retigabine reduced mechanical hypersensitivity in STZ-diabetic are in line with these findings.…”

Changes in expression of Kv7.5 and Kv7.2 channels in dorsal root ganglion neurons in the streptozotocin rat model of painful diabetic neuropathy

“…Our findings of downregulation of K v 7.5 channel protein expression in small DRG neurons are partly consistent with those of [20] who also found significant decreases in the expression of K v 7.2, K v 7.3 and K v 7.5 channels at both mRNA and protein levels in STZ rats. K v 7.5 expression was also found to be down-regulated in DRG neurons following sciatic nerve axotomy [17].…”

“…However, other studies reported no change (or even a transient increase) in the expression of the K v 7.2, K v 7.3 or K v 7.5 channel proteins in DRG neurons following spinal nerve injury (see [15]. As far as we know, only one recent study examined expression of these subunits in DRG neurons in the rat STZ model of DPNP and found significant decreases in K v 7.2, Kv7.3 and Kv7.5 at both mRNA and protein levels [20]. Thus, further studies are required to unravel the apparent discrepancies between the aforementioned studies.…”

Nociceptor Signalling through ion Channel Regulation via GPCRs

“…Enhancing KV7 currents exerts analgesic effects since hyperpolarizing the resting membrane potential of nociceptors decreases neuronal excitability [220,221]. Similarly, inhibiting KV7 currents is proalgesic since concomitant depolarization of the resting membrane potential enhances neuronal firing [222,223].…”