Persistent pain is a prominent symptom of diabetic neuropathy (DN), the most common complication of diabetes mellitus. Around 50% of the diabetic population have some degree of diabetic neuropathy (American Diabetes Association). The pathophysiology of diabetic neuropathic pain (DNP) is poorly understood. DNP is believed to be partly due to abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. Although, the underlying cellular and molecular mechanisms of this hyperexcitability are unknown, certain voltage-gated potassium (Kv) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that normally stabilize the resting membrane potential are likely to be involved. Thus expression of Kv channel subunits including Kv1.4, Kv3.4, Kv4.2, and Kv4.3 was reduced in DRG neurons in a rat model of DNP (Cao et al. 2010). Expression of Kv7.2 has also been shown to decrease after nerve injury (Rose et al. 2011). Here we used: a) immunofluorescence to examine whether expression of Kv7 and HCN channel subunits changes in a rat model of DNP, and, b) behavioural testing to examine whether activation of Kv7 channels with retigabine alleviates pain hypersensitivity in this model. All in vivo procedures were regulated under the Animals (Scientific Procedures) Act, 1986. Diabetes was induced in adult male Sprague Dawley rats (around 200g) by an injection of streptozotocin (STZ) (60 mg/kg, i.p.). Using anti-Kv7.2, Kv7.5, HCN1, HCN2 and HCN3 antibodies, we performed immunofluorescence on L4/5 DRG from diabetic and control rats (n=4). We also examined the effects of the Kv7 channel activator, retigabine (7.5 mg/kg, i.p.) and the Kv7 channel blocker XE991 (3 mg/kg, i.p.) on evoked pain behaviours (heat and mechanical hypersensitivity) in diabetic rats 5 weeks post STZ (n=7-10). Data were presented as mean±SEM. An unpaired t test was used to analyse immunofluorescence data, and two-way repeated measures ANOVA was used to analyse behavioural data. Comparison of normalised densitometric data from control and STZ DRG showed no significant change in Kv7.2 or Kv7.5 immunoreactivity between the two groups. Similar analysis of HCN staining showed no significant change between control and STZ groups for HCN1 or HCN3, but HCN2 immunoreactivity was significantly increased in the STZ group compared to controls (P<0.001). Behavioural studies showed retigabine caused a non-significant reversal in mechanical hypersensitivity associated with DNP. This analgesic effect of retigabine was completely reversed by the Kv7 antagonist XE991 (P<0.05). Whether blocking HCN channels also reduces pain hypersensitivity associated with DNP remains to be determined. Taken together these findings suggest that modulation of neuronal Kv7 and HCN channels may have therapeutic potential for the treatment of DNP.