Effects of ketamine on acute somatic nociception in wild-type and N-methyl-d-aspartate (NMDA) receptor ɛ1 subunit knockout mice

Petrenko, Andrey B.; Yamakura, Tomohiro; Askalany, Ahmed R.; Kohno, Tatsuro; Sakimura, Kenji; Baba, Hiroshi

doi:10.1016/j.neuropharm.2005.11.019

Cited by 18 publications

(12 citation statements)

References 37 publications

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“…If any, effects of ketamine on normal pain perception occur only at much higher doses in human and animal experiments (Arendt-Nielsen et al, 1995;Petrenko et al, 2006;Kern et al, 2008). These results are in line with recent findings, demonstrating that inhibition of the protein tyrosine kinase Src, a key enhancer of NMDAR function, blocks neuropathic and inflammatory pain responses, but does not affect basal sensory thresholds or acute nociceptive responses in mice (Liu et al, 2008).…”

Section: Effects Of (S)-ketamine and (S)-norketamine On Somatosensorysupporting

confidence: 87%

Effects of low‐dose intranasal (S)‐ketamine in patients with neuropathic pain

Huge

Lauchart

Magerl

et al. 2010

European Journal of Pain

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Section: Effects Of (S)-ketamine and (S)-norketamine On Somatosensorysupporting

confidence: 87%

Effects of low‐dose intranasal (S)‐ketamine in patients with neuropathic pain

Huge

Lauchart

Magerl

et al. 2010

European Journal of Pain

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“…The activation of NMDA receptors initiates hyperexcitability of spinal neurons that cause abnormal responses to peripheral stimuli (5,10,24,56). NMDA receptor antagonists have been shown to attenuate injury-induced hyperalgesia in animal models; however, their clinical use is compromised by their narrow therapeutic window and adverse side effect such as motor weakness and hallucinations (44).…”

Section: Discussionmentioning

confidence: 99%

Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain

Jergová

Gajavelli

Pathak

et al. 2016

Pain

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Neuropathic pain induced by spinal cord injury (SCI) is clinically challenging with inadequate long-term treatment options. Partial pain relief offered by pharmacologic treatment is often counterbalanced by adverse effects after prolonged use in chronic pain patients. Cell-based therapy for neuropathic pain using GABAergic neuronal progenitor cells (NPC) has the potential to overcome untoward effects of systemic pharmacotherapy while enhancing analgesic potency due to local activation of GABAergic signaling in the spinal cord. However, multifactorial anomalies underlying chronic pain will likely require simultaneous targeting of multiple mechanisms. Here we explore the analgesic potential of genetically modified rat embryonic GABAergic NPCs releasing a peptidergic NMDA receptor antagonist, Serine1-histogranin (SHG), thus targeting both spinal hyperexcitability and reduced inhibitory processes. Recombinant NPCs were designed using either lentiviral or adeno-associated-viral vectors (AAV2/8) encoding single and multimeric (6 copies of SHG) cDNA. Intraspinal injection of recombinant cells elicited enhanced analgesic effects compared to nonrecombinant NPCs in spinal cord injury-induced pain in rats. Moreover, potent and sustained antinociception was achieved, even following a 5 weeks post-injury delay, using recombinant multimeric NPCs. Intrathecal injection of SHG antibody attenuated analgesic effects of the recombinant grafts suggesting active participation of SHG in these antinociceptive effects. Immunoblots and immunocytochemical assays indicated ongoing recombinant peptide production and secretion in the grafted host spinal cords. These results support the potential for engineered NPCs grafted into the spinal dorsal horn to alleviate chronic neuropathic pain.

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“…For example, MK-801 is a more potent NMDA receptor inhibitor than ketamine but has little hypnotic action, even at high doses (Daniell, 1990; Kelland et al, 1993; Stabernack et al, 2003; Irifune et al, 2007). Moreover, mice with deletions of the widely expressed NMDA receptor NR2A subunit fail to exhibit specific deficits in ketamine action (Petrenko et al, 2004; 2006; Sato et al, 2005). Other identified substrates for ketamine action are modulated at supraclinical concentrations (e.g., Kv channels; Schnoebel et al, 2005) and/or they are expressed in brain regions that are unlikely to mediate hypnotic effects (e.g., α6 GABA A receptors in cerebellum; Hevers et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine

Shu²,

2009

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Ketamine has important anesthetic, analgesic, and psychotropic actions. It is widely believed that NMDA receptor inhibition accounts for ketamine actions, but there remains a dearth of behavioral evidence to support this hypothesis. Here, we present an alternative, behaviorally relevant molecular substrate for anesthetic effects of ketamine: the HCN1 pacemaker channels that underlie a neuronal hyperpolarization-activated cationic current (I h ). Ketamine caused subunit-specific inhibition of recombinant HCN1-containing channels and neuronal I h at clinically relevant concentrations; the channels were more potently inhibited by S-(ϩ)-ketamine than racemic ketamine, consistent with anesthetic actions of the compounds. In cortical pyramidal neurons from wild-type, but not HCN1 knock-out mice, ketamine induced membrane hyperpolarization and enhanced dendritosomatic synaptic coupling; both effects are known to promote cortical synchronization and support slow cortical rhythms, like those accompanying anesthetic-induced hypnosis. Accordingly, we found that the potency for ketamine to provoke a loss-of-righting reflex, a behavioral correlate of hypnosis, was strongly reduced in HCN1 knock-out mice. In addition, hypnotic sensitivity to two other intravenous anesthetics in HCN1 knock-out mice matched effects on HCN1 channels; propofol selectively inhibited HCN1 channels and propofol sensitivity was diminished in HCN1 knock-out mice, whereas etomidate had no effect on HCN1 channels and hypnotic sensitivity to etomidate was unaffected by HCN1 gene deletion. These data advance HCN1 channels as a novel molecular target for ketamine, provide a plausible neuronal mechanism for enhanced cortical synchronization during anesthetic-induced hypnosis and suggest that HCN1 channels might contribute to other unexplained actions of ketamine.

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Effects of ketamine on acute somatic nociception in wild-type and N-methyl-d-aspartate (NMDA) receptor ɛ1 subunit knockout mice

Cited by 18 publications

References 37 publications

Effects of low‐dose intranasal (S)‐ketamine in patients with neuropathic pain

Effects of low‐dose intranasal (S)‐ketamine in patients with neuropathic pain

Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain

HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine

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