Antiallodynic and Antihyperalgesic Effects of Selective Competitive GLU_K5 (GluR5) Ionotropic Glutamate Receptor Antagonists in the Capsaicin and Carrageenan Models in Rats

Abstract

GLU K5 kainate receptor subunits are abundant in pain pathways, including dorsal root ganglia and spinothalamic neurons, as well as in the thalamus and brain stem. A growing body of evidence indicates that the GLU K5 kainate receptor subtype plays a prominent role in pain transmission, particularly in persistent pain. In the present studies, compounds from a novel series of amino acid GLU K5 receptor antagonists were evaluated for their effectiveness in reversing capsaicin-induced mechanical allodynia as well as carrageenan-induced thermal hyperalgesia. In vitro, the amino acid compounds were efficacious in blocking glutamate-evoked calcium flux in cells expressing GLU K5 but not GLU K6 or GLU A2 , homomeric receptors. Electrophysiologically, the compounds exhibited selectivity for kainate receptors in dorsal root ganglion cells relative to ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide and N-methyl-D-aspartate receptors in hippocampal pyramidal neurons. The amino acid compounds were poorly efficacious in the pain tests after s.c. or p.o. administration. However, compounds were highly efficacious after central intracisternal administration, and the rank order of potencies correlated with their rank order of affinities at GLU K5 receptors determined in vitro, indicating that the lack of activity after systemic administration was due to poor oral bioavailability. To increase oral bioavailability, isobutyl or 2-ethylbutyl ester prodrugs of the parent amino acids were prepared. The prodrugs, which produced robust plasma levels of parent amino acids, were highly efficacious in the capsaicin and carrageenan tests. The present studies provide further evidence that selective Glu K5 kainate receptor subtype antagonists can reverse allodynia and hyperalgesia, particularly in persistent pain states.Ionotropic glutamate receptors are ion channel-coupled receptors that are classified based on their activation by specific agonists: NMDA, AMPA (McBain and Mayer, 1994), and kainate receptors (e.g., Hollmann and Heinemann, 1994). Moreover, multiple receptor subunit proteins for each class of ionotropic receptors have been identified and cloned (Hollmann and Heinemann, 1994). Of the AMPA and kainate ionotropic glutamate receptor subunit proteins cloned, GLU A1-A4 are AMPA-sensitive, whereas GLU K5-K7 and GLU K1-K2 are AMPA-insensitive and kainate-preferring (Seeburg, 1993;Hollmann and Heinemann, 1994). Activation of these ionotropic receptors is important for normal central nervous system functions such as synaptogenesis, synaptic plasticity, and the development of functional neural circuits. However, excessive levels of glutamate may be responsible for pathological central nervous system processes, including neurodegeneration following stroke and ischemia and, abnormal processing of pain-related information (McBain and Mayer, 1994). Therefore, the development of ionotropic glutamate receptor antagonists has been viewed as a potentially important therapeutic strategy for the treatment of many neurolog...

Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive antagonists

“…KARs are tetrameric assemblies of GluK1–5 subunits (Collingridge et al, 2009) and have been implicated in various functions in the central nervous system (Jane et al, 2009; Lerma, 2006; Pinheiro and Mulle, 2006). In addition, KARs and in particular those containing the GluK1 subunit have been implicated in a number of neurological conditions, such as chronic pain (Jones et al, 2006; Simmons et al, 1998), migraine (Weiss et al, 2006), epilepsy (Smolders et al, 2002) and neurodegeneration (O’Neill et al, 2000) as well as in psychiatric conditions, such as schizophrenia (Beneyto et al, 2007) and anxiety (Alt et al, 2007). …”

Kainate Receptor Signaling in Pain Pathways

“…LY293558 also reduced mechanical hyperalgesia in a rat model of postoperative pain (paw incision) when administered intrathecally (Lee et al, 2006). Interestingly, the antinociceptive efficacy of the decahydroisoquinolines correlated well with their activity on GluK1-containing receptors specifically when introduced centrally into the cisterna magna (Jones et al, 2006), suggesting that supraspinal KARs comprised an important site of action of the antagonists.…”

“…3A). Esterified prodrugs of LY382884 and a less selective decahydroisoquinoline, LY293558, were analgesic when delivered orally in the formalin model as well as inflammatory thermal and mechanical hyperalgesia models of pain (Dominguez et al, 2005;Jones et al, 2006). LY293558 also reduced mechanical hyperalgesia in a rat model of postoperative pain (paw incision) when administered intrathecally (Lee et al, 2006).…”

The utility of ionotropic glutamate receptor antagonists in the treatment of nociception induced by epidural glutamate infusion in rats

“…[122628] Similarly, it now appears that small amounts of a kainate or NMDA receptor antagonists deposited near the DRG can also treat sciatic pain related to the presence of glutamate emanating from disc.…”