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

Abstract

Diabetic peripheral neuropathic pain (DPNP) is the most devastating complication of diabetes mellitus. Unfortunately, successful therapy for DPNP remains a challenge because its pathogenesis is still elusive. However, DPNP is believed to be due partly to abnormal hyperexcitability of dorsal root ganglion (DRG) neurons, but the relative contributions of specific functional subtypes remain largely unknown. Here, using the strepotozotocin (STZ) rat model of DPNP induced by a STZ injection (60 mg/kg, i.p), and intracellular recordings of action potentials (APs) from DRG neurons in anesthetized rats, we examined electrophysiological changes in C-and Aβ-nociceptive and Aβ-low threshold mechanoreceptive (LTM) neurons that may contribute to DPNP. Compared with control, we found in STZ-rats with established pain hypersensitivity (5 weeks post-STZ) several significant changes including: (a) A 23% increase in the incidence of spontaneous activity (SA) in Aβ-LTMs (but not C-mechanosensitive nociceptors) that may cause dysesthesias/paresthesia suffered by DPNP patients, (b) membrane hyperpolarization and a ∼85% reduction in SA rate in Aβ-LTMs by K v 7 channel activation with retigabine (6 mg/kg, i.v.) suggesting that K v 7/M channels may be involved in mechanisms of SA generation in Aβ-LTMs, (c) decreases in AP duration and in duration and amplitude of afterhyperpolarization (AHP) in C-and/or Aβ-nociceptors. These faster AP and AHP kinetics may lead to repetitive firing and an increase in afferent input to the CNS and thereby contribute to DPNP development, and (d) a decrease in the electrical thresholds of Aβ-nociceptors that may contribute to their sensitization, and thus to the resulting hypersensitivity associated with DPNP.

Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity

“…In experimental animals, peripheral nerve damage, such as that generated by chronic constriction or section of the sciatic nerve, induces pain-related behaviours that serve as a model for human neuropathic pain 3,4 . Seven or more days of sciatic nerve injury promote an enduring increase in the excitability of first order primary afferent neurons [5][6][7][8] . These become chronically active and release a variety of mediators (cytokines, chemokines, neuropeptides, ATP and growth factors) that predispose spinal microglia to a more 'activated' state [9][10][11][12][13][14] .…”

Peripheral Mechanisms of Neuropathic Pain—The Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain

“…The data shows as well abnormal axonal sprouting of myelinated Aβ axons in the spinal dorsal horn. The peripheral receptive fields of Aβ neurons are more excitable, which in summary contributes to the generation and maintenance of the peripheral, central sensitization and NP [42,51,52]. The pathology in tactile Aβ neurons, resulting in nociceptive responses to normally innocuous cutaneous stimuli, is observed in humans with NP and clinically refers to allodynia and spontaneous pain following peripheral nerve injury [8,53,54].…”

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

“…Using the STZ model of DPNP, in vivo electrophysiology and behavioral assays, we have recently provided evidence implicating K v 7 channels in hyperexcitability of DRG neurons [21] and the associated pain hypersensitivity [22]. In the present immunohistochemical study, we sought to examine whether expression of K v 7.2 and/or K v 7.5 channels is altered in DRG neurons in STZ rats.…”