Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam

  title={Effects of the $\alpha$2/$\alpha$3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam},
  author={Megan J Moerke and Guanguan Li and Lalit K Golani and James M Cook and Sidney Stevens Negus},
  journal={Behavioural Pharmacology},
  pages={452 - 461}
This study examined effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 in an assay of pain-related behavioral depression. Adult, male Sprague-Dawley rats responded for electrical brain stimulation in a frequency-rate intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of 1.8% lactic acid served as an acute noxious stimulus to depress ICSS. Effects of KRM-II-81 were evaluated in the absence and presence of the acid noxious stimulus… Expand
The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats
Findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Expand
The α2,3-selective potentiators of GABAA receptors, KRM-II-81 and MP-III-80, produce anxiolytic-like effects and block chemotherapy-induced hyperalgesia in mice without tolerance development
Subchronic dosing for 22 days with KRM-II-81 and MP-III-80 demonstrated enduring analgesic efficacy without tolerance development; the antihyperalgesic effects of gabapentin showed evidence of tolerance development. Expand
The Positive Allosteric Modulator of α2/3-Containing GABAA Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury
  • J. Witkin, G. Li, +8 authors X. Jin
  • Medicine
  • The Journal of Pharmacology and Experimental Therapeutics
  • 2019
The imidizodiazepine KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy. Expand
Effects of Repeated Treatment with Monoamine-Transporter-Inhibitor Antidepressants on Pain-Related Depression of Intracranial Self-Stimulation in Rats
Results support effectiveness of bupropion to alleviate signs of pain-related behavioral depression in rats and further suggest that nortriptyline and citalopram produce a more gradual onset of antinociception during repeated treatment. Expand
Effects of repeated treatment with monoamine-transporter-inhibitor antidepressants on pain-related depression of intracranial self-stimulation in rats
These results support effectiveness of bupropion to alleviate signs of pain-related behavioral depression in rats and further suggest that nortriptyline and citalopram produce significant but less reliable effects. Expand
Targeting nitric oxide production in microglia with novel imidazodiazepines for non-sedative pain treatment.
The GABAergic system of immortalized mouse and human microglia is characterized using electrophysiology and qRT-PCR to identify a new class of non-sedative drug candidates for inflammatory pain. Expand


Abuse-related effects of subtype-selective GABAA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats
These results are concordant with drug self-administration studies in monkeys in suggesting that GABAA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1- selective GAB AA P AMs. Expand
Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys
Results suggest that α1 subunit-containing GABAA receptors may have a role in the reinforcing effects of benzodiazepine-type compounds in monkeys with a history of sedative-anxiolytic/benzodiazepines self-administration, whereas α3 sub unit- containing GAB AA receptors may be important mediators of the reinforcing effect. Expand
Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats
  • A. Kwilasz, S. Negus
  • Chemistry, Medicine
  • Journal of Pharmacology and Experimental Therapeutics
  • 2012
Thepoor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans. Expand
Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABAA receptor ligand MP-III-024
γ-Aminobutyric acid type A (GABAA) receptors are located in spinal nociceptive circuits where they modulate the transmission of pain sensory signals from the periphery to higher centers.Expand
Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABAA Receptor Positive Allosteric Modulator.
KRM-II-81 is a selective α2/α3 subtype GABAA PAM with significant antinociceptive effects in chemical stimulation-induced pain in mice, and similar efficacy at α1/α2/ α3 subtypes with similar potency is demonstrated. Expand
Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity
Pain is associated with stimulation of some behaviors and depression of others, and μ-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays ofExpand
Comparison of the Novel Subtype-Selective GABAA Receptor-Positive Allosteric Modulator NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with Diazepam, Zolpidem, Bretazenil, and Gaboxadol in Rat Models of Inflammatory and Neuropathic Pain
The robust therapeutic window seen with NS11394 in animals suggests that compounds with this in vitro selectivity profile could have potential benefit in clinical treatment of pain in humans. Expand
GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics.
  • J. Atack
  • Chemistry, Medicine
  • Current topics in medicinal chemistry
  • 2011
T attempts were made to identify subtype-selective compounds that modulate α2/α3 but not α1 receptor function with the prediction that such compounds would be non-sedating anxiolytics, and a structurally-related class of imidazopyridines was explored. Expand
HZ166, a novel GABAA receptor subtype-selective benzodiazepine site ligand, is antihyperalgesic in mouse models of inflammatory and neuropathic pain
HZ166 showed a dose-dependent anti-hyperalgesic effect in mouse models of neuropathic and inflammatory pain, triggered by chronic constriction injury of the sciatic nerve and by subcutaneous injection of the yeast extract zymosan A, respectively, providing further evidence that compounds selective for α2- and α3-GABA(A) receptors might constitute a novel class of analgesics suitable for the treatment of chronic pain. Expand
Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice
It is concluded that systemic diazepam exerts a genuine antihyperalgesic effect, which depends on spinal GABAA receptors containing α2 and/or α3 subunits, which reduced formalin‐induced flinching in wild‐type mice. Expand