Blockade of Glycine Transporter (GlyT) 2, but Not GlyT1, Ameliorates Dynamic and Static Mechanical Allodynia in Mice With Herpetic or Postherpetic Pain

Abstract

Abstract.Glycine is an inhibitory neurotransmitter in the spinal dorsal horn and its extracellular concentration is regulated by glial glycine transporter (GlyT) 1 and neuronal GlyT2. This study was conducted to elucidate the effects of intrathecal injections of GlyT1 and GlyT2 inhibitors on two distinct types of mechanical allodynia, dynamic and static allodynia, in mice with herpetic or postherpetic pain. The GlyT2 inhibitor ALX1393, but not the GlyT1 inhibitor sarcosine, suppressed dynamic and static allodynia at the herpetic and postherpetic stages. Intrathecal ALX1393 suppressed dynamic allodynia induced by intrathecal strychnine and N -methyl-D -aspartate (NMDA). Intrathecal sarcosine suppressed dynamic allodynia induced by intrathecal strychnine, but not NMDA. Expression level of GlyT1, but not GlyT2, mRNA in the lumbar dorsal horn was decreased at the herpetic and postherpetic stages. Glycine receptor α 1-subunit mRNA was decreased in the lumbar dorsal horn at the herpetic, but not postherpetic stage, without alteration in α 3-subunit mRNA. The results suggest that GlyT2 is a potential target for treatment of dynamic and static allodynia in patients with herpes zoster and postherpetic neuralgia. The lack of efficacy of GlyT1 inhibitor may be explained by activation of NMDA receptors and the down-regulation of GlyT1 in the lumbar dorsal horn.

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

“…A loss of GABAergic and glycinergic synaptic inhibition in this region has been recognized as an important process in the development and maintenance of chronic pain (23,24). Pharmacological blockade of glycine transporters in the spinal cord increases either glycinergic and/or GABAergic neurotransmission in vivo and produces pain relief in mouse pain models (25)(26)(27)(28)(29)(30). This suggests that glycine transport can modulate the function of glycinergic dorsal horn neurons.…”

Glycine transport inhibitors for the treatment of pain

“…Furthermore, no effects on locomotor activity, motor behaviour in the rotorod test, or the righting reflex were observed in these studies [38]. ALX1393 has also been studied in a mouse model of allodynia caused by herpetic and postherpetic pain induced by infection with herpes simplex virus [41]. Intrathecal ALX1393 injections alleviate allodynia within 60 minutes after injection, but return to baseline pain states after 24 hours.…”

“…ALX1393 has been studied in animal models of pain using either intravenous or intrathecal injections [38][39][40][41][42]. Although intrathecal ALX1393 inhibits acute thermal and mechanical pain responses, it is considerably more potent against sensitized responses (tonic phase of the formalin test) [38,40,42].…”

Safety, Tolerability, and Pharmacokinetic Characteristics of a Novel Nonopioid Analgesic, VVZ‐149 Injections in Healthy Volunteers: A First‐in‐Class, First‐in‐Human Study

“…To prepare the samples for analysis, a sample of either plasma or urine was mixed with acetonitrile in the presence of an internal standard (VVZ-149d 9 and VVZ-368d 9 ; Vivozon Inc., Seoul, Korea). The mixture was then vortexed for 1 minute and centrifuged for 5 minutes at 13 000 rpm.…”

“…6,8 The inhibitory signals caused by GlyT2 inhibition depress pain signal transmission from sensory organs to the central nervous system, thereby exerting antinociceptive effects. 9,10 However, only a few studies have investigated GlyT2 inhibitors as new drug candidates, and the studied candidates have shown fatal in vivo toxicity at efficacious dosage ranges. 11 Targeting multiple analgesic pathways could induce greater synergistic effects than targeting a single pathway.…”