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Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain.
Neurosci Lett 2008; 445(3):214-9NL

Abstract

Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain. Since the concentration of glycine in the synaptic cleft is controlled by specialized proteins, the glycine transporters GlyT1 and GlyT2, manipulation of this system might have significant effects on nociception. In the present study, we investigated the effects of the spinally applied glycine transporter inhibitors ALX 5407 (GlyT1) and ALX 1393 (GlyT2) on nociceptive behavior in the chronic constriction injury model of neuropathic pain in male Wistar rats. After implementation of neuropathy, the animals were injected with three dosages of ALX 5407 and ALX 1393 (10, 50 and 100 microg) via an intrathecal catheter (n = 8 each). Subsequently, nociceptive behavior was evaluated regarding thermal hyperalgesia (Hargreaves method) and mechanical sensitization (von Frey filaments) over 240 min after application. Inhibition of GlyT1 by ALX 5407 had differential dose-dependent effects. While the highest and the lowest concentrations were antinociceptive, the medium dose evoked pronociceptive effects. The GlyT2 inhibitor ALX 1393 was only effective in the highest concentration at which it exerted significant antinociception. However, in the same dose, ALX 1393 caused remarkable side effects such as respiratory depression and motor deficits in three animals. Our findings indicate that inhibition of glycine transporters is capable of evoking significant effects on nociceptive behavior in neuropathic pain. Whether glycine transporter inhibitors have the capability to gain clinical relevance as analgesic compounds on the long run has to be elucidated in further investigations.

Authors+Show Affiliations

Department of Anesthesiology, University Hospital Düsseldorf, Düsseldorf, Germany. Henning.Hermanns@uni-duesseldorf.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18793697

Citation

Hermanns, Henning, et al. "Differential Effects of Spinally Applied Glycine Transporter Inhibitors On Nociception in a Rat Model of Neuropathic Pain." Neuroscience Letters, vol. 445, no. 3, 2008, pp. 214-9.
Hermanns H, Muth-Selbach U, Williams R, et al. Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain. Neurosci Lett. 2008;445(3):214-9.
Hermanns, H., Muth-Selbach, U., Williams, R., Krug, S., Lipfert, P., Werdehausen, R., ... Bauer, I. (2008). Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain. Neuroscience Letters, 445(3), pp. 214-9. doi:10.1016/j.neulet.2008.09.012.
Hermanns H, et al. Differential Effects of Spinally Applied Glycine Transporter Inhibitors On Nociception in a Rat Model of Neuropathic Pain. Neurosci Lett. 2008 Nov 21;445(3):214-9. PubMed PMID: 18793697.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain. AU - Hermanns,Henning, AU - Muth-Selbach,Uta, AU - Williams,Ruth, AU - Krug,Sabrina, AU - Lipfert,Peter, AU - Werdehausen,Robert, AU - Braun,Sebastian, AU - Bauer,Inge, Y1 - 2008/09/11/ PY - 2008/08/14/received PY - 2008/09/06/revised PY - 2008/09/08/accepted PY - 2008/9/17/pubmed PY - 2009/4/17/medline PY - 2008/9/17/entrez SP - 214 EP - 9 JF - Neuroscience letters JO - Neurosci. Lett. VL - 445 IS - 3 N2 - Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain. Since the concentration of glycine in the synaptic cleft is controlled by specialized proteins, the glycine transporters GlyT1 and GlyT2, manipulation of this system might have significant effects on nociception. In the present study, we investigated the effects of the spinally applied glycine transporter inhibitors ALX 5407 (GlyT1) and ALX 1393 (GlyT2) on nociceptive behavior in the chronic constriction injury model of neuropathic pain in male Wistar rats. After implementation of neuropathy, the animals were injected with three dosages of ALX 5407 and ALX 1393 (10, 50 and 100 microg) via an intrathecal catheter (n = 8 each). Subsequently, nociceptive behavior was evaluated regarding thermal hyperalgesia (Hargreaves method) and mechanical sensitization (von Frey filaments) over 240 min after application. Inhibition of GlyT1 by ALX 5407 had differential dose-dependent effects. While the highest and the lowest concentrations were antinociceptive, the medium dose evoked pronociceptive effects. The GlyT2 inhibitor ALX 1393 was only effective in the highest concentration at which it exerted significant antinociception. However, in the same dose, ALX 1393 caused remarkable side effects such as respiratory depression and motor deficits in three animals. Our findings indicate that inhibition of glycine transporters is capable of evoking significant effects on nociceptive behavior in neuropathic pain. Whether glycine transporter inhibitors have the capability to gain clinical relevance as analgesic compounds on the long run has to be elucidated in further investigations. SN - 0304-3940 UR - https://www.unboundmedicine.com/medline/citation/18793697/Differential_effects_of_spinally_applied_glycine_transporter_inhibitors_on_nociception_in_a_rat_model_of_neuropathic_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3940(08)01245-7 DB - PRIME DP - Unbound Medicine ER -