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

Background And Purpose: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu receptor agonist prodrug were investigated.

Experimental Approach: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu receptor agonist LY2934747.

TRPV3 in Drug Development.

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception.

Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications.

Background: Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD).

Methods: Because of continuously increasing evidence for a neuromodulatory role of endocannabinoids in dopamine-related pathophysiological responses, we assessed endocannabinoid signaling in DAT KO mice and evaluated the ability of endocannabinoid ligands to normalize behavioral deficits, namely spontaneous hyperlocomotion in these mice.

Results: In DAT KO mice, we found markedly reduced anandamide levels, specifically in striatum, the dopamine nerve terminal region.

Antihyperalgesic effects of the muscarinic receptor ligand vedaclidine in models involving central sensitization in rats.

It is well established that muscarinic cholinergic agonists produce antinociceptive effects in a number of acute pain models. However, relatively little is known about the effects of muscarinic receptor agonists in models which involve central sensitization in pain pathways. The purpose of the present studies was to evaluate the effects of vedaclidine, a muscarinic receptor mixed agonist/antagonist across receptor subtypes, in models involving central sensitization.