British journal of pharmacology 2017 02 08() doi 10.1111/bph.13740
BACKGROUND AND PURPOSE
A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3 receptor agonist prodrug were investigated.
After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent, and subtype-selective mGlu2/3 receptor agonist LY2934747. Behavioral assessments of allodynia, hyperalgesia, or nocifensive behaviors in preclinical pain models were determined after administration of LY2969822 of 0.3 – 10 mg/kg. In addition, the ability of i.v. administrated LY2934747 to modulate dorsal horn spinal cord wide dynamic range (WDR) neurons in spinal nerve ligated (SNL) rats was assessed.
Following treatment with LY2934747, the spontaneous activity and the electrically-evoked wind-up of WDR neurons in rats that had undergone spinal nerve ligation and developed mechanical allodynia was suppressed. In a model of sensitization, orally administered LY2969822 prevented the nociceptive behaviors induced with intraplantar formalin injection with an ED50 value of 3.2 mg/kg. The on-target nature of this effect was confirmed by blockade with an mGlu2/3 receptor antagonist. LY2969822 prevented capsaicin-induced tactile hypersensitivity and reversed the SNL-induced tactile hypersensitivity and reversed CFA – induced mechanical hyperalgesia. The mGlu2/3 receptor agonist prodrug demonstrated efficacy in visceral pain models, including a colorectal distension model and partially preventing the nocifensive behaviors in the mouse acetic acid writhing model.
Following oral administration of the prodrug LY2969822 the mGlu2/3 receptor agonist LY2934747 was formed and attenuated pain behaviors across a broad range of pre-clinical pain models.