Peripheral administration of selective GlyT2 inhibitor, oleoyl-D-lysine, reverses chronic neuropathic pain but not acute or inflammatory pain in male mice
Wilson, BS
Peiser-Oliver, J
Gillis, A
Evans, S
Alamein, C
Mostyn, SN
Shimmon, S
Rawling, T
Christie, MJ
Vandenberg, RJ
Mohammadi, SA
- Publisher:
- AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
- Publication Type:
- Journal Article
- Citation:
- J Pharmacol Exp Ther, 2022, 382, (3), pp. 246-255
- Issue Date:
- 2022-09
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Peripheral administration of selective GlyT2 inhibitor, oleoyl-D-lysine, reverses chronic neuropathic pain but not acute or inflammatory pain in male mice.pdf | Accepted version | 408.92 kB | Adobe PDF |
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Wilson, BS | |
dc.contributor.author | Peiser-Oliver, J | |
dc.contributor.author | Gillis, A | |
dc.contributor.author | Evans, S | |
dc.contributor.author | Alamein, C | |
dc.contributor.author | Mostyn, SN | |
dc.contributor.author | Shimmon, S | |
dc.contributor.author |
Rawling, T |
|
dc.contributor.author | Christie, MJ | |
dc.contributor.author | Vandenberg, RJ | |
dc.contributor.author | Mohammadi, SA | |
dc.date.accessioned | 2023-04-14T01:06:09Z | |
dc.date.available | 2022-06-13 | |
dc.date.available | 2023-04-14T01:06:09Z | |
dc.date.issued | 2022-09 | |
dc.identifier.citation | J Pharmacol Exp Ther, 2022, 382, (3), pp. 246-255 | |
dc.identifier.issn | 0022-3565 | |
dc.identifier.issn | 1521-0103 | |
dc.identifier.uri | http://hdl.handle.net/10453/169788 | |
dc.description.abstract | Aberrations in spinal glycinergic signaling are a feature of pain chronification. Normalizing these changes by inhibiting glycine transporter (GlyT)-2 is a promising treatment strategy. However, existing GlyT2 inhibitors (e.g., ORG25543) are limited by narrow therapeutic windows and severe dose-limiting side effects, such as convulsions, and are therefore poor candidates for clinical development. Here, intraperitoneally administered oleoyl-D-lysine, a lipid-based GlyT2 inhibitor, was characterized in mouse models of acute (hot plate), inflammatory (complete Freund's adjuvant), and chronic neuropathic (chronic constriction injury) pain. Side effects were also assessed on a numerical rating score, convulsions score, for motor incoordination (rotarod), and for respiratory depression (whole body plethysmography). Oleoyl-D-lysine produced near complete antiallodynia for chronic neuropathic pain, but no antiallodynia/analgesia in inflammatory or acute pain. No side effects were seen at the peak analgesic dose, 30 mg/kg. Mild side effects were observed at the highest dose, 100 mg/kg, on the numerical rating score, but no convulsions. These results contrasted markedly with ORG25543, which reached less than 50% reduction in allodynia score only at the lethal/near-lethal dose of 50 mg/kg. At this dose, ORG25543 caused maximal side effects on the numerical rating score and severe convulsions. Oleoyl-D-lysine (30 mg/kg) did not cause any respiratory depression, a problematic side effect of opiates. These results show the safe and effective reversal of neuropathic pain in mice by oleoyl-D-lysine and provide evidence for a distinct role of glycine in chronic pain over acute or short-term pain conditions. SIGNIFICANCE STATEMENT: Partially inhibiting glycine transporter (GlyT)-2 can alleviate chronic pain by restoring lost glycinergic function. Novel lipid-based GlyT2 inhibitor ol-D-lys is safe and effective in alleviating neuropathic pain, but not inflammatory or acute pain. Clinical application of GlyT2 inhibitors may be better suited to chronic neuropathic pain over other pain aetiologies. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.publisher | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS | |
dc.relation | http://purl.org/au-research/grants/nhmrc/APP1144429 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/GNT1082570 | |
dc.relation.ispartof | J Pharmacol Exp Ther | |
dc.relation.isbasedon | 10.1124/jpet.122.001265 | |
dc.rights | info:eu-repo/semantics/closedAccess | |
dc.subject | 1115 Pharmacology and Pharmaceutical Sciences | |
dc.subject.classification | Pharmacology & Pharmacy | |
dc.subject.mesh | Acute Pain | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Chronic Pain | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Glycine Plasma Membrane Transport Proteins | |
dc.subject.mesh | Hyperalgesia | |
dc.subject.mesh | Lipids | |
dc.subject.mesh | Lysine | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Neuralgia | |
dc.subject.mesh | Respiratory Insufficiency | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Respiratory Insufficiency | |
dc.subject.mesh | Neuralgia | |
dc.subject.mesh | Hyperalgesia | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Lipids | |
dc.subject.mesh | Lysine | |
dc.subject.mesh | Male | |
dc.subject.mesh | Glycine Plasma Membrane Transport Proteins | |
dc.subject.mesh | Chronic Pain | |
dc.subject.mesh | Acute Pain | |
dc.subject.mesh | Acute Pain | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Chronic Pain | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Glycine Plasma Membrane Transport Proteins | |
dc.subject.mesh | Hyperalgesia | |
dc.subject.mesh | Lipids | |
dc.subject.mesh | Lysine | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Neuralgia | |
dc.subject.mesh | Respiratory Insufficiency | |
dc.title | Peripheral administration of selective GlyT2 inhibitor, oleoyl-D-lysine, reverses chronic neuropathic pain but not acute or inflammatory pain in male mice | |
dc.title.alternative | Peripheral Administration of Selective Glycine Transporter-2 Inhibitor, Oleoyl-D-Lysine, Reverses Chronic Neuropathic Pain but Not Acute or Inflammatory Pain in Male Mice | |
dc.type | Journal Article | |
utslib.citation.volume | 382 | |
utslib.location.activity | United States | |
utslib.for | 1115 Pharmacology and Pharmaceutical Sciences | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences | |
utslib.copyright.status | closed_access | * |
dc.date.updated | 2023-04-14T01:06:07Z | |
pubs.issue | 3 | |
pubs.publication-status | Published | |
pubs.volume | 382 | |
utslib.citation.issue | 3 |
Abstract:
Aberrations in spinal glycinergic signaling are a feature of pain chronification. Normalizing these changes by inhibiting glycine transporter (GlyT)-2 is a promising treatment strategy. However, existing GlyT2 inhibitors (e.g., ORG25543) are limited by narrow therapeutic windows and severe dose-limiting side effects, such as convulsions, and are therefore poor candidates for clinical development. Here, intraperitoneally administered oleoyl-D-lysine, a lipid-based GlyT2 inhibitor, was characterized in mouse models of acute (hot plate), inflammatory (complete Freund's adjuvant), and chronic neuropathic (chronic constriction injury) pain. Side effects were also assessed on a numerical rating score, convulsions score, for motor incoordination (rotarod), and for respiratory depression (whole body plethysmography). Oleoyl-D-lysine produced near complete antiallodynia for chronic neuropathic pain, but no antiallodynia/analgesia in inflammatory or acute pain. No side effects were seen at the peak analgesic dose, 30 mg/kg. Mild side effects were observed at the highest dose, 100 mg/kg, on the numerical rating score, but no convulsions. These results contrasted markedly with ORG25543, which reached less than 50% reduction in allodynia score only at the lethal/near-lethal dose of 50 mg/kg. At this dose, ORG25543 caused maximal side effects on the numerical rating score and severe convulsions. Oleoyl-D-lysine (30 mg/kg) did not cause any respiratory depression, a problematic side effect of opiates. These results show the safe and effective reversal of neuropathic pain in mice by oleoyl-D-lysine and provide evidence for a distinct role of glycine in chronic pain over acute or short-term pain conditions. SIGNIFICANCE STATEMENT: Partially inhibiting glycine transporter (GlyT)-2 can alleviate chronic pain by restoring lost glycinergic function. Novel lipid-based GlyT2 inhibitor ol-D-lys is safe and effective in alleviating neuropathic pain, but not inflammatory or acute pain. Clinical application of GlyT2 inhibitors may be better suited to chronic neuropathic pain over other pain aetiologies.
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