AMPA/Kainate Antagonist LY293558 Reduces Capsaicin-evoked Hyperalgesia but Not Pain in Normal Skin in Humans

Sang, Christine N.; Hostetter, Meredith P.; Gracely, Richard H.; Chappell, Amy S.; Schoepp, Darryle D.; Lee, Gloria; Whitcup, Scott M.; Caruso, Rafael C.; Max, Mitchell B.

doi:10.1097/00000542-199811000-00005

Cited by 124 publications

(60 citation statements)

References 40 publications

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“…onists acting on GluR5-containing kainate receptors reduce pain-related behaviors in formalin and capsaicin models of hyperalgesia in rats (Sang et al, 1998;Simmons et al, 1998), capsaicin-induced hyperalgesia and allodynia in humans (Sang et al, 1998), and postoperative pain (Gilron et al, 2000). GluR5-selective antagonists also have potential for therapeutic use in the treatment of migraine.…”

Section: Marine-derived Ligands For Glutamate Receptors 1073mentioning

confidence: 99%

Divergent Pharmacological Activity of Novel Marine-Derived Excitatory Amino Acids on Glutamate Receptors

Sanders¹,

Ito²,

Settimo³

et al. 2005

J Pharmacol Exp Ther

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Kainate receptors show a particular affinity for a variety of natural source compounds, including dysiherbaine (DH), a potent agonist derived from the marine sponge Dysidea herbacea. In this study, we characterized the pharmacological activity and structural basis for subunit selectivity of neodysiherbaine (neoDH) and MSVIII-19, which are natural and synthetic analogs of DH, respectively. NeoDH and MSVIII-19 differ from DH in the composition of two functional groups that confer specificity and selectivity for ionotropic glutamate receptors. In radioligand binding assays, neoDH displayed a 15-to 25-fold lower affinity relative to that of DH for glutamate receptor (GluR)5 and GluR6 kainate receptor subunits but a 7-fold higher affinity for kainate (KA)2 subunits, whereas MSVIII-19 displaced [ 3 H]kainate only from GluR5 subunits but not GluR6 or KA2 subunits. NeoDH was an agonist for kainate and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in patch-clamp recordings; in contrast, MSVIII-19 acted as a potent antagonist for homomeric GluR5 receptor currents with weaker activity on other kainate and AMPA receptors. Neither neoDH nor MSVIII-19 activated group I metabotropic GluRs. Homology modeling suggests that two critical amino acids confer the high degree of selectivity between the dysiherbaine analogs and the GluR5 and KA2 subunits. In summary, these data describe the pharmacological activity of two new compounds, one of which is a selective GluR5 receptor antagonist that will be of use for understanding native receptor function and designing more selective ligands for kainate receptors.

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Section: Marine-derived Ligands For Glutamate Receptors 1073mentioning

confidence: 99%

Divergent Pharmacological Activity of Novel Marine-Derived Excitatory Amino Acids on Glutamate Receptors

Sanders¹,

Ito²,

Settimo³

et al. 2005

J Pharmacol Exp Ther

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“…In humans oral dosing has indicated some effects upon afferent evoked hyperalgesia [214]. vi) The AMPA receptor is composed of GluR1-GluR4 subunits.…”

Section: Future Directions For Spinal Nmda Antagonistsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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“…The decahydroisoquinoline LY293558 was efficacious in alleviation of inflammatory pain caused by capsaicin injection (Sang et al, 1998), postoperative pain (Gilron et al, 2000), and migraine pain and associated conditions (Sang et al, 2004), with minimal side effects and acceptable tolerance. Beneficial effects were observed with LY293558 (also known as tezampanel or NGX424) in a phase II clinical trial focused on alleviation of migraine pain (Murphy et al, 2008).…”

Section: Kars As Therapeutic Targetsmentioning

confidence: 99%

Kainate Receptor Signaling in Pain Pathways

Bhangoo

Swanson

2012

Mol Pharmacol

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Receptors and channels that underlie nociceptive signaling constitute potential sites of intervention for treatment of chronic pain states. The kainate receptor family of glutamate-gated ion channels represents one such candidate set of molecules. They have a prominent role in modulation of excitatory signaling between sensory and spinal cord neurons. Kainate receptors are also expressed throughout central pain neuraxis, where their functional contributions to neural integration are less clearly defined. Pharmacological inhibition or genetic ablation of kainate receptor activity reduces pain behaviors in a number of animal models of chronic pain, and small clinical trials have been conducted using several orthosteric antagonists. This review will cover kainate receptor function and participation in pain signaling as well as the pharmacological studies supporting further consideration as potential targets for therapeutic development.

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AMPA/Kainate Antagonist LY293558 Reduces Capsaicin-evoked Hyperalgesia but Not Pain in Normal Skin in Humans

Abstract: The authors infer that AMPA-KA receptor blockade reduces the spinal neuron sensitization that mediates capsaicin-evoked pain and allodynia. The low incidence of side effects at effective doses of LY293558 suggests that this class of drugs may prove to be useful in clinical pain states.

Cited by 124 publications

References 40 publications

Divergent Pharmacological Activity of Novel Marine-Derived Excitatory Amino Acids on Glutamate Receptors

Divergent Pharmacological Activity of Novel Marine-Derived Excitatory Amino Acids on Glutamate Receptors

Current and Future Issues in the development of spinal agents for the management of pain

Kainate Receptor Signaling in Pain Pathways

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