Activation of K_v7 channels with the anticonvulsant retigabine alleviates neuropathic pain behaviour in the streptozotocin rat model of diabetic neuropathy

Abstract

Diabetic peripheral neuropathy (DPN) is the most incapacitating complication of diabetes mellitus. Up to 50% of patients with DPN develop peripheral neuropathic pain (PNP). The underlying ionic and molecular mechanisms of diabetic PNP (DPNP) are poorly understood. However, voltage gated potassium (K v 7) channels which have been implicated in the pathogenesis of other types of PNP are likely to be involved. Here we examined, in the streptozotocin (STZ) rat model of DPNP, whether activating the Kv7 channels with a potent activator retigabine (ezogabine) would reverse/attenuate behavioural signs of DPNP. STZ rats exhibited behavioural indices of mechanical and heat hypersensitivity, but not cold hypersensitivity or spontaneous pain, 35 days after STZ injection. Retigabine given at a dose of 15 mg/kg (but not at 7.5 mg/ kg, i.p.) significantly attenuated mechanical, but not heat hypersensitivity in DPNP rats, and was as effective as the positive control gabapentin. This analgesic effect of retigabine was completely reversed by the K v 7/M channel blocker XE991 (3 mg/kg, i.p.) indicating that the anti-allodynic effects of retigabine were mediated by K v 7 channels. In conclusion, the findings suggest that Kv7 channels are involved in DPNP pathogenesis, and that strategies that target their activation may prove to be effective in treating DPNP.

Cutaneous Aβ-Non-nociceptive, but Not C-Nociceptive, Dorsal Root Ganglion Neurons Exhibit Spontaneous Activity in the Streptozotocin Rat Model of Painful Diabetic Neuropathy in vivo

“…We used the STZ rat model of DPNP that involves a single injection of STZ (60 mg/kg, i.p.) after an overnight fast to reduce competition between glucose and STZ for uptake into pancreatic β-cells as reported previously (see Djouhri et al, 2019). It is noteworthy that hypoinsulinemia and hyperglycemia caused by STZ is due to its cytotoxicity to pancreatic β cells.…”

“…The STZ model (model of type 1 diabetes) is more commonly used than other models of DPNP because of its low cost, rapid induction, greater stability and relative lack of toxicity to other organs (Skovso, 2014). More imoprtantly, the STZ model is known to exhibit long lasting behavioral signs of DPNP including mechanical and heat hypersensitivity (see Djouhri et al, 2019 and section "Discussion").…”

“…Pain behavioral testing was conducted on 10 STZ rats by an experimenter blind to the various treatment animal groups as reported recently (Djouhri et al, 2019). Briefly, paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and cold escape/nocifensive behavior, were assessed on the left hind paw of each STZ rat.…”

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain

“…Moreover, impairment of expression of K v 7.2 induces thermal and mechanical hyperalgesia in naïve animals (King et al, 2014). In line with this, the K v 7 activator, retigabine has been shown to alleviate neuropathic pain behavior in a rodent model of diabetic neuropathy (Djouhri et al, 2019). The effectiveness of retigabine paralleled that of gabapentin and its effect was reversed by the K v 7/M-channel blocker, XE991.…”

“…↓Protein and mRNA by IHC and ISH (Tsantoulas et al, 2012)* siRNA-mediated knock-down of K v 9.1 in naive rats leads to neuropathic pain behaviors (Tsantoulas et al, 2012) Kv9. (King et al, 2014) G9a inhibitors attenuate pain hypersensitivity (Laumet et al, 2015) Gain of function mutation in Kv7.2 reduces pain in "burning man syndrome" (Mis et al, 2019) Anti-allodynic effect of retigabine (Blackburn-Munro and Jensen, 2003;Dermody et al, 2012;Djouhri et al, 2019) A-currents…”