(2R,6R)-Hydroxynorketamine restores postsynaptic localization of AMPAR in the prelimbic cortex to provide sustained pain relief

JIN, Tingting; Ng, Hei Lui Lhotse; Jiang, Yanjun; Ho, Idy H. T.; Zou, Yawen; Li, Qian; Zhang, Lin; Chen, Huarong; Wang, Jie; Zhou, Jingying; Gin, Tony; Wu, William Ka Kei; Chan, Matthew T.V.; Liu, Xiaodong

doi:10.21203/rs.3.rs-2261014/v1

Cited by 1 publication

(3 citation statements)

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“…5,16,19 Contrary to the studies in murine models of depression, we observed an decrease in hippocampal BDNF following (2R,6R)-HNK administration in murine models of pain. Our findings concur with those of Jin et al 10 who demonstrated using transcriptomic analysis of the prelimbic cortex that SNI pain was associated with increased BDNF signaling, abnormal dendritic spine organization, and reduced AMPAR activity and that (2R,6R)-HNK administration decreased BDNF in the prelimbic cortex when compared to saline. The authors suggested that the analgesic activity of (2R,6R)-HNK depends on modulation of the BDNF/ARC/AMPA axis possibly through reduction in BDNF (TrkB) pathway activity.…”

Section: Discussionsupporting

confidence: 93%

“…The authors suggested that the analgesic activity of (2R,6R)-HNK depends on modulation of the BDNF/ARC/AMPA axis possibly through reduction in BDNF (TrkB) pathway activity. 10 Our finding of a decreased ratio of BDNF in the hippocampus supports the aforementioned hypothesis.…”

Section: Discussionsupporting

confidence: 87%

“…8 The analgesic efficacy of (2R,6R)-HNK in the SNI model has been replicated by Yost et al, 9 who also demonstrated that the analgesia was amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and not opioid-dependent. Jin et al 10 examined transcriptomic changes of the BDNF/activity-regulated cytoskeleton-protein (ARC)/α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) axis using microarray analysis in the prelimbic cortex in the SNI pain model. The finding of the study suggested that SNI-associated pain was driven by increased BDNF signaling and reduced AMPAR activity and postulated that (2R,6R)-HNK analgesia was through restoration of prelimbic cortex to periaqueductal gray connectivity via decreased BDNF.…”

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confidence: 99%

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A Pharmacological Evaluation of the Analgesic Effect and Hippocampal Protein Modulation of the Ketamine Metabolite (2R,6R)-Hydroxynorketamine in Murine Pain Models

Das

Basovich

Thomas

et al. 2023

Anesthesia &Amp; Analgesia

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BACKGROUND:The ketamine metabolite (2R,6R)-hydroxynorketamine ([2R,6R]-HNK) has analgesic efficacy in murine models of acute, neuropathic, and chronic pain. The purpose of this study was to evaluate the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) dependence of (2R,6R)-HNK analgesia and protein changes in the hippocampus in murine pain models administered (2R,6R)-HNK or saline. METHODS: All mice were CD-1 IGS outbred mice. Male and female mice underwent plantar incision (PI) (n = 60), spared nerve injury (SNI) (n = 64), or tibial fracture (TF) (n = 40) surgery on the left hind limb. Mechanical allodynia was assessed using calibrated von Frey filaments. Mice were randomized to receive saline, naloxone, or the brain-penetrating AMPA blocker (1,2,3,quinoxaline-7-sulfonamide [NBQX]) before (2R,6R)-HNK 10 mg/kg, and this was repeated for 3 consecutive days. The area under the paw withdrawal threshold by time curve for days 0 to 3 (AUC 0-3d ) was calculated using trapezoidal integration. The AUC 0-3d was converted to percent antiallodynic effect using the baseline and pretreatment values as 0% and 100%. In separate experiments, a single dose of (2R,6R)-HNK 10 mg/kg or saline was administered to naive mice (n = 20) and 2 doses to PI (n = 40), SNI injury (n = 40), or TF (n = 40) mice. Naive mice were tested for ambulation, rearing, and motor strength. Immunoblot studies of the right hippocampal tissue were performed to evaluate the ratios of glutamate ionotropic receptor (AMPA) type subunit 1 (GluA1), glutamate ionotropic receptor (AMPA) type subunit 2 (GluA2), phosphorylated voltage-gated potassium channel 2.1 (p-Kv2.1), phosphorylated-calcium/calmodulin-dependent protein kinase II (p-CaMKII), brain-derived neurotrophic factor (BDNF), phosphorylated protein kinase B (p-AKT), phosphorylated extracellular signal-regulated kinase (p-ERK), CXC chemokine receptor 4 (CXCR4), phosphorylated eukaryotic translation initiation factor 2 subunit 1 (p-EIF2SI), and phosphorylated eukaryotic translation initiation factor 4E (p-EIF4E) to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). RESULTS: No model-specific gender difference in antiallodynic responses before (2R,6R)-HNK administration was observed. The antiallodynic AUC 0-3d of (2R,6R)-HNK was decreased by NBQX but not with pretreatment with naloxone or saline. The adjusted mean (95% confidence interval [CI]) antiallodynic effect of (2R,6R)-HNK in the PI, SNI, and TF models was 40.7% (34.1%-47.3%), 55.1% (48.7%-61.5%), and 54.7% (46.5%-63.0%), greater in the SNI, difference 14.3% (95% CI, 3.1-25.6; P = .007) and TF, difference 13.9% (95% CI, 1.9-26.0; P = .019) compared to the PI model. No effect of (2R,6R)-HNK on ambulation, rearing, or motor coordination was observed. Administration of (2R,6R)-HNK was associated with increased GluA1, GluA2, p-Kv2.1, and p-CaMKII and decreased BDNF ratios in the hippocampus, with model-specific variations in proteins involved in other pain pathways. CONCLUSIONS: (2R,6R)-HNK analgesia is AMPA-dependent, and (2R,6R)-HNK affected gluta...

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