Broad spectrum efficacy with LY2969822, an oral prodrug of metabotropic glutamate 2/3 receptor agonist LY2934747, in rodent pain models

Abstract

Following oral administration of the prodrug LY2969822, the mGlu receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models.

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats

“…Both 30 and 100 mg/kg KRM-II-8, p.o, significantly increased paw withdrawal thresholds in these rats as did the positive control drug gabapentin (75 mg/kg, p.o.). The time-course for gabapentin was generally as previously reported with a trend for activity at 1 hr (Johnson et al, 2017).…”

“…The present report provides data on effects of KRM-II-81 on nociceptive behaviors controlled by the inflammatory impact of formalin injection and on pain-related behaviors of rats undergoing chronic ligation of spinal nerves L5/6. Both models have been used to evaluate a host of other drugs that act as analgesics or are candidate molecules for pain therapeutics (Carter and Shieh, 2010;Johnson et al, 2017;Tjølsen et al, 1992;Wang and Wang, 2003).…”

“…Behaviorally, this neuronal excitability manifests as biphasic bouts of nocifensive responding. In the present experiments, male, Rats were used to assess the ability of KRM-II-81 to reduce tactile hypersensitivity induced by formalin injection into the rat paw by methods previously described (Johnson et al, 2017). Briefly, rats were acclimated to the test apparatus (SR-Lab Startle Response System, San Diego Instruments, San Diego, CA) and then injected with 50 μL of 5% formalin solution (in 0.9% saline) into the plantar surface of the right hind paw.…”

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice

“…Metabotropic glutamate receptors are known to modulate pain sensitivity ( Chiechio and Nicoletti, 2012 ; Palazzo et al, 2014 ; Chiechio, 2016 ). In particular analgesia can be obtained by either blocking group I mGlu receptors, namely mGlu1 and mGlu5 ( Walker et al, 2001 ; Sasikumar et al, 2010 ; Bennett et al, 2012 ; Brumfield et al, 2012 ) or by activating group II and group III mGlu receptors ( Chiechio and Nicoletti, 2012 ; Chiechio, 2016 ; Johnson et al, 2017 ). Also, we have demonstrated that epigenetic drugs that increase the expression of mGlu2 receptors are analgesic in models of persistent pain ( Chiechio et al, 2002 , 2009 , 2010 ; Zammataro et al, 2014 ).…”

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

“…In a model of persistent colonic hypersensitivity induced colonic anaphylaxis, hypersensitivity was demonstrated as increased synaptic facilitation in the anterior cingulate from the thalamus, which was inhibited by local infusion of an antagonist targeting the NR2B subunit of NMDA receptors (Wang et al, 2015 ). In mice, a prodrug of a mGlu2/3 agonist dose-dependently reduced basal colonic sensitivity, inflammation-induced colonic hypersensitivity, and total writhing behaviors (Johnson et al, 2017 ). Intrathecal administration of suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, at L6-S2 reversed swim stress-induced colonic hypersensitivity thorough changes in mGlu2/3 receptor expression in female rats (Cao et al, 2016 ).…”