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

Abstract

Diabetic peripheral neuropathic pain (DPNP), the most debilitating complication of diabetes mellitus, is resistant to current therapy. The pathogenesis of DPNP is still elusive, but several mechanisms have been proposed including abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. The underlying molecular mechanisms of such aberrant hyperexcitability are incompletely understood. Using the streptozotocin (STZ) rat model of DPNP, we have recently provided evidence implicating neuronal K v 7 channels that normally exert a powerful stabilizing influence on neuronal excitability, in the abnormal hyperexcitability of DRG neurons and in pain hypersensitivity associated with DPNP. In the present immunohistochemical study, we sought to determine whether K v 7.2 and/or K v 7.5 channel expression is altered in DRG neurons in STZ rats. We found 35 days post-STZ: (1) a significant decrease in K v 7.5-immunoreactivity in small (< 30 μm) DRG neurons (both IB4 positive and IB4 negative) and medium-sized (30−40 μm) neurons, and (2) a significant increase in K v 7.2-immunoreactivity in small (< 30 μm) neurons, and a non-significant increase in medium/large neurons. The decrease in K v 7.5 channel expression in small and medium-sized DRG neurons in STZ rats is likely to contribute to the mechanisms of hyperexcitability of these neurons and thereby to the resulting pain hypersensitivity associated with DPNP. The upregulation of K v 7.2 subunit in small DRG neurons may be an activity dependent compensatory mechanism to limit STZ-induced hyperexcitability of DRG neurons and the associated pain hypersensitivity. The findings support the notion that K v 7 channels may represent a novel target for DPNP treatment.

Kv7 Channel Activators Flupirtine and ML213 Alleviate Neuropathic Pain Behavior in the Streptozotocin Rat Model of Diabetic Neuropathy

“… 30 Indeed, there is accumulating evidence that a decrease in expression and/or function of K v channels, especially those that are tonically active near the resting membrane potential such as K v 7 channels, contributes to hyperexcitability of sensory neurons associated with nerve injury/dysfunction. K v 7 channels may contribute to such hyperexcitability because: (a) they underlie the slowly activating, non-inactivating outward M current (I M ) that normally exerts a powerful stabilizing influence on neuronal excitability (see eg, 31–34 ) (b) they have been found within both peripheral and central components of the nociceptive pathway including nociceptive peripheral nerve endings and nociceptive dorsal roots/central terminals; 35–37 for review see, 38 (c) they (K v 7.2 and/or K v 7.5 subunits) were found to be down-regulated in DRG neurons after spinal nerve injury (see 38 ) and in STZ-rats, 18 (d) their inhibition with a specific blocker XE991 increases excitability of DRG neurons, 39 , 40 and (e) their activators/openers reduce excitability of nociceptive neurons, and block/reduce nerve injury-induced SA in sensory fibers; 41–43 (see 38 for review) and in a subpopulation of DRG neurons in STZ-rats. 12 …”

“…We used the STZ model because it is more commonly used than other models of diabetes mellitus and because of its rapid induction, greater stability and low cost as reported previously. 12 , 15 , 18 It involves a single injection of STZ (60 mg/kg, i.p.) after an overnight fast to reduce competition between STZ and glucose for uptake into pancreatic β-cells.…”

“…within both peripheral and central components of the nociceptive pathway including nociceptive peripheral nerve endings and nociceptive dorsal roots/central terminals; [35][36][37] for review see, 38 (c) they (K v 7.2 and/or K v 7.5 subunits) were found to be down-regulated in DRG neurons after spinal nerve injury (see 38 ) and in STZ-rats, 18 (d) their inhibition with a specific blocker XE991 increases excitability of DRG neurons, 39,40 and (e) their activators/openers reduce excitability of nociceptive neurons, and block/reduce nerve injury-induced SA in sensory fibers; [41][42][43] (see 38 for review) and in a subpopulation of DRG neurons in STZ-rats. 12 Anti-Allodynic Effects of Flupirtine and ML213 in STZ Rats Activation of K v 7 channels has been proven as a useful strategy for attenuation of chronic pain in animal models (for reviews see e.g.…”