a-803467 and Neuralgia

Methylglyoxal is known to be associated with the development of nephropathy, retinopathy, and other complications in diabetes. The present study tested the hypothesis that endogenously increased levels of methylglyoxal in diabetes are causally associated with the induction of neuropathic pain.. Streptozotocin- and methylglyoxal-induced pain models were established in rats, and the anti-nociceptive effects of the methylglyoxal scavenging agents, selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, and Nav1.8 antagonist were tested.. Systemic injection of streptozotocin in rats induced a prolonged increase in plasma methylglyoxal by approximately 60%, which was correlated with the progressive development of mechanical allodynia and thermal hyperalgesia. Local subcutaneous injection of methylglyoxal into the hindpaw produced dose-dependent and biphasic flinching nociceptive responses, which resembled formaldehyde (formalin)-induced nociception. The local methylglyoxal nociception was significantly blocked by co-injection into the hindpaw of the selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, A967079, and the Nav1.8 antagonist, A803467. Co-incubation with the methylglyoxal scavengers, aminoguanidine, d-arginine, and metformin, reduced the level of free methylglyoxal by more than 90%, and injection of their incubation solutions into the hindpaw produced negligible (3-17%) nociception. Like the clinically effective anti-diabetic neuropathic pain drug gabapentin, systemic injection of aminoguanidine, d-arginine, and metformin at doses that effectively inhibit paw-injected methylglyoxal-induced nociception significantly blocked streptozotocin-induced mechanical allodynia.. Endogenously increased methylglyoxal may mediate diabetic neuropathic pain via activation of both TRPA1 and Nav1.8 expressed on primary afferent sensory neurons, and injection of methylglyoxal into the hindpaw may serve as a simple and robust model for testing the anti-diabetic pain drugs.

Topics: Analgesics; Aniline Compounds; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Furans; Hyperalgesia; Hypoglycemic Agents; Male; NAV1.8 Voltage-Gated Sodium Channel; Neuralgia; Oximes; Pain Measurement; Pyruvaldehyde; Rats; Rats, Wistar; TRPA1 Cation Channel; TRPC Cation Channels

Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration.

Topics: Administration, Oral; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Ganglia, Spinal; Humans; Microsomes; NAV1.8 Voltage-Gated Sodium Channel; Neuralgia; Neurons; Pyrazines; Rats; Sodium Channel Blockers; Sodium Channels; Structure-Activity Relationship