a-803467 and Diabetic-Neuropathies

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

The streptozocin-induced diabetic rat is a model of chronic pain that shows signs of hyperalgesia and allodynia and may replicate signs in diabetic humans. Here we investigated the antinociceptive effects of A803467, a highly selective blocker of Nav1.8 channels, in diabetic rats with painful neuropathy. We systemically (intraperitoneal) or locally (intraplantar) administered A803467 (or lidocaine, a nonselective sodium channel blocker, as a control) to diabetic rats with hyperalgesia and allodynia and then measured thermal latencies and mechanical thresholds. With intraperitoneal administration, A803467 led to 6-fold greater reduction of hyperalgesia and 2-fold greater reduction of allodynia than did lidocaine. Whereas the antihyperalgesic effects of lidocaine and A803467 were similar after intraplantar administration, A803467 (1 mg) was at least 2 times more effective as an antiallodynic than was lidocaine (0.5 mg). These results suggest that compared with lidocaine, systemic or local blockade of Nav1.8 channels by A803467 may more effectively relieve hyperalgesia and allodynia in diabetic neuropathy.

Topics: Analgesics; Aniline Compounds; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Female; Furans; Humans; Hyperalgesia; Lidocaine; NAV1.8 Voltage-Gated Sodium Channel; Rats; Rats, Wistar; Sodium Channel Blockers