The Competitive a-Amino-3-Hydroxy-5-Methylisoxazole-4- Propionate Receptor Antagonist LY293558 Attenuates and Reverses Analgesic Tolerance to Morphine But Not to Delta or Kappa Opioids

Antagonists of the NMDA type of excitatory amino acid (EAA) receptor attenuate or reverse the development of tolerance to the analgesic effects of the mu opioid agonist morphine, the delta-1 opioid agonist DPDPE but not the kappa-1 agonist U50,488H or the kappa-3 agonist naloxone benzoylhydrazone. The role of the AMPA subtype of EAA receptor in analgesic tolerance was examined using LY293558, a selective competitive antagonist that is active after systemic administration. Administration of morphine, DPDPE, or U50,488H three times daily for 3 days according to an escalating dosing schedule resulted in analgesic tolerance as indicated by an increase in analgesic ED50 values using the tail-flick test in mice. Analgesic tolerance was attenuated when mice received a continuous subcutaneous infusion of LY293558 at doses of 30, 45 or 60 mg/kg/24 hr via an osmotic pump concurrent with the morphine treatment. Continuous subcutaneous infusion of LY293558 (45 mg/kg/24 hr) also reversed established morphine tolerance. In contrast, continuous subcutaneous infusion of the highest dose of LY293558 (60 mg/kg/24 hr) was ineffective in preventing the development of analgesic tolerance to DPDPE or U50,488H. Continuous subcutaneous infusion of LY293558 (60 mg/kg/24 hr) for 3 days protected mice from generalized convulsions produced by the selective AMPA agonist ATPA, indicating that the dosage of LY293558 that attenuated morphine tolerance was effective as an antagonist at AMPA receptors. These results demonstrate that AMPA receptors may play a role in the development and maintenance of morphine, but not DPDPE or U50,488H, analgesic tolerance. Excitatory amino acids including glutamate and aspartate are neurotransmitters in the vertebrate central nervous system (Bettler and Mulle, 1995; Watkins, 1994). The NMDA, AMPA and kainate receptors are named on the basis of the selective agonists used for their initial characterization. These three types are directly coupled to cation channels (ionotropic receptors). AMPA receptors are involved in the generation of the fast component of synaptic transmission, and NMDA receptors contribute to a slow component of repetitive synaptic activity generated primarily by AMPA and other non-NMDA EAA receptor coupled channels (Watkins, 1994). Pharmacological, electrophysiological and molecular cloning studies have demonstrated that these EAA receptors are functionally and constitutively distinct (Bettler and Mulle, 1995; Watkins, 1994). Through the use of selective competitive and noncompetitive antagonists that are active after systemic administration, it is well established that NMDA receptor blockade can attenuate or reverse the development of morphine tolerance in the mouse or rat (see reviews by Elliott et al., 1995; Pasternak and Inturrisi, 1995). The potential clinical utility of NMDA receptor antagonists is enhanced by the observation that these antagonists act directly on the processes underlying the development of morphine tolerance and do not potentiate morphine analgesia (Elliott et al., 1995; Pasternak and Inturrisi, 1995). The recent cloning of three separate genes encoding opioid receptors supports pharmacological studies indicating that opioids exert their effects at mu, delta and kappa receptor types (Knapp et al., 1995; Mansour et al., 1995). Using liReceived for publication May 16, 1997. 1 This work was supported by NIDA Grant DA01457. B.K. and G.M. are Aaron Diamond Postdoctoral Fellows, and this work was supported in part by a grant from the Aaron Diamond Foundation. C.E.I. is a recipient of a Research Scientist Award from NIDA (DA00198). 2 D. Leander, personal communication. ABBREVIATIONS: ACPC, 1-aminocyclopropane carboxylic acid; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, aamino-3-hydroxy-5-tert-butyl-4-isoxazolepropionic acid; CI, confidence interval; DPDPE, [D-Pen,D-Pen]enkephalin; EAA, excitatory amino acid; i.c.v., intracerebroventricular; LY293558, (3S,4aR,6R,8aR)-6-[2-(1(2)0H-tetrazole-6-yl)ethyl]decahydroisoquinoline-3-carboxylic acid; NMDA, Nmethyl-D-aspartate; s.c., subcutaneous; U50,488H, trans-(1)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide methane sulfonate hydrate; NPC17742, 2R,4R,5S-(2-amino-4,5-(1,2-cycloxexyl)-7-phosphonoheptanoic acid; TF, tail-flick. 0022-3565/97/2833-1249$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 283, No. 3 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 283:1249–1255, 1997 1249 at A PE T Jornals on A ril 8, 2017 jpet.asjournals.org D ow nladed from gands with relative selectivity, it has been shown that analgesia can be mediated by each of the three opioid receptors (Pasternak, 1993; Porreca and Burks, 1993; Suh and Tseng, 1990). Although morphine exerts its analgesic effects primarily at the mu receptor type (Matthes et al., 1996), U50,488H is the prototypic kappa-1 receptor agonist (Von Voigtlander et al., 1983). The opioid effects of the conformationally restricted enkephalin analog DPDPE and [D-Ala]deltorphin II are differentially affected by several selective delta receptor antagonists and therefore characterized as delta-1 and delta-2 opioid receptor agonists, respectively (Jiang et al., 1990; Suh and Tseng, 1990). Tolerance to the analgesic effects of opioids after repeated administration occurs independently of changes in the potency of opioids acting at other receptor types. For example, tolerance to the analgesic effects of morphine after chronic administration does not produce a concomitant loss in the analgesic potency of U50,488H, nor does U50,488H tolerance produce cross-tolerance to morphine analgesia (Von Voigtlander et al., 1983). Reciprocal cross-tolerance is also not observed among DPDPE, [D-Ala]deltorphin II and the mu receptor selective opioid DAMGO (Mattia et al., 1991). Thus, the mechanisms of opioid analgesic tolerance for each opioid receptor type appear to be selective. This differential organization is thought to underlie the selective ability of NMDA receptor antagonists to prevent analgesic tolerance. In our laboratory, the competitive and noncompetitive NMDA receptor antagonists LY274614 and MK-801, respectively, as well as the nitric oxide synthase inhibitor N-nitro-L-arginine were able to attenuate and reverse analgesic tolerance to morphine but not to U50,488H or to the kappa-3 agonist naloxone benzylhydrazone (Elliott et al., 1994, 1995; Tiseo et al., 1994; Tiseo and Inturrisi, 1993). LY235959 (the active isomer of LY274614) and MK-801 attenuated tolerance to morphine but not to the delta-2 agonist [D-Ala,Glu]deltorphin (Bilsky et al., 1996), whereas blockade of the allosteric glycine site of the NMDA receptor by ACPC prevents tolerance to the analgesic effects of morphine and DPDPE but not to U50,488H (Kolesnikov et al., 1994). NPC17742, a competitive NMDA receptor antagonist that differs structurally from the LY274614 and MK801 type compounds, prevents morphineand U50,488H-induced analgesic tolerance (Kolesnikov et al., 1993). In contrast to the extensive studies with NMDA receptor antagonists, the role of AMPA receptors in opioid tolerance is unknown. This may reflect the investigational constraints of the available AMPA receptor antagonists, which either have limited solubility or are not active after systemic administration. Recently, Ornstein et al. (1993) reported the synthesis of LY215490, a structurally novel and systemically active competitive AMPA receptor antagonist. Resolution of LY215490 yields LY293558, the levorotatory isomer that is the active AMPA receptor antagonist. In ligand binding assays, LY293558 selectively displaces AMPA receptor ligands. In these assays, the affinity of LY293558 at AMPA receptors is 9-fold greater than that at NMDA receptors and 21-fold greater than at kainate receptors (Schoepp et al., 1995). In the in vitro functional assays (rat cortical wedge preparation and EEA agonist-evoked release of H-norepinephrine), LY293558 and/or LY215490 demonstrates selective AMPA receptor antagonist activity (Schoepp et al., 1995). Both LY293558 and LY215490 were anticonvulsant against maximal electroshock seizures in mice (Ornstein et al., 1993) and protect against the convulsions produced by ATPA, a selective AMPA receptor agonist. The aim of the present study was to examine the role of AMPA receptors in the development and maintenance of opioid tolerance in mice using LY293558. Because opioid agonists differ in their sensitivity to the modulation of tolerance by NMDA receptor antagonists (Bilsky et al., 1996; Elliott et al., 1995, 1994; Kolesnikov et al., 1994; Pasternak and Inturrisi, 1995), the effects of LY293558 on analgesic tolerance to morphine, U50,488H, DPDPE and [DAla2]deltorphin II were assessed. We also determined whether LY293558, administered by osmotic pump, had any effects on motor performance or was able to protect mice against convulsions produced by ATPA. Materials and Methods Subjects. Male adult CD-1 mice (25–35 g, Charles River, Kingston, NY) were housed five to a cage and maintained on a 12/12-hr light/dark cycle in a temperature-controlled environment with unrestricted food and water. Each treatment condition was replicated once, and each treatment group consisted of 10 mice unless other-