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Behavioral Sensitization to Kainic Acid and Quisqualic Acid in Mice: Comparison to NMDA and Substance P Responses

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Behavioral Sensitization to Kainic Acid and Quisqualic Acid in Mice: Comparison to NMDA and Substance P Responses The Journal of Neuroscience, October 1991, 1 I(1 0): 3111-3123 Behavioral Sensitization to Kainic Acid and Quisqualic Acid in Mice: Comparison to NMDA and Substance P Responses Xiaofeng Sun and Alice A. Larson Department of Veterinary Biology, University of Minnesota, St. Paul. Minnesota 55108 Substance P (SP) and the excitatory amino acid (EAA) ag- acid (EAA) receptor subtypesthat have beenclassified based on onists NMDA, kainic acid (KA), or quisqualic acid (Quis) each the preferential activation ofthese receptorsby the EAAagonists produce a transient, caudally directed biting and scratching NMDA, kainate (KA), and quisqualate (Quis) (Evans et al., response (CBS) in mice after their intrathecal injection. We 1978,1979; McLennan and Lodge, 1979;Foster and Fagg, 1984). have previously shown that repeated injections of SP result In the spinal cord, SP is thought to act as a primary afferent in a decrease in the intensity of CBS, or desensitization. The transmitter that is especially important in nociceptive trans- goals of the present study were (1) to determine whether mission (Lembeck, 1953; Salt and Hill, 1983; Besson and desensitization also develops to the CBS behavior produced Chaouch, 1987). Intrathecal administration of SP to mice elicits by EAAs in the spinal cord, (2) to characterize the role of a dose-dependent,caudally directed biting and scratching(CBS) interneurons in desensitization, and (3) to examine possible behavior (Hylden and Wilcox, 198 1; Piercey et al., 198 1) that interactions between EAAs and SP. While injection of NMDA has been postulated to reflect aversive activity (Sakurada et al., at 2 min intervals resulted in desensitization to its CBS be- 1988; Wilcox, 1988). This behavioral model has been widely havioral effect, behavioral responses to repeated injections used as a tool to investigate the pharmacological effects of ex- of KA or Quis increased in intensity, exhibiting sensitization. citatory compounds in the CNS, especially with respect to pain The NMDA antagonist DL-2-amino-5-phosphonovaleric acid transmission. Using this paradigm, we have demonstrated that failed to alter sensitization to either KA or Quis but inhibited repeated intrathecal injections of SP result in a decreasedin- behaviors produced by SP and NMDA, suggesting an NMDA- tensity of CBS behavior with each subsequentinjection, that is, mediated component in SP-induced behavior. Concanavalin desensitization (Larson, 1988). Behavioral desensitization is a A, which is reported to block desensitization to the electro- decreasein the responseto an agonist and can be brought about physiologic effect of Quis, blocked sensitization to the be- by a variety of mechanisms.SP, for example, typically exhibits havioral effects of both Quis and KA. Strychnine, bicuculline, a rapid desensitization in several systems(Laufer et al., 1988) and !&aminovaleric acid each inhibited desensitization to SP and is thought to result from decreasedactivity at neurokinin- 1 and NMDA, supporting the notion of recruitment of inhibitory receptors. The ability of SP to induce hyperalgesiain rats has transmitters in the attenuation of NMDA and SP activity. Pre- also beenfound to exhibit desensitization (Moochhala and Saw- treatment with capsaicin selectively inhibited the develop- ynok, 1984). Desensitization to the CBS behavioral effects of ment of behavioral sensitization to KA, suggesting an in- SP appears to result from the action of inhibitory metabolites volvement of small-diameter C-fibers in the enhancement of that attenuate the responseto SP rather than downregulation of responsivity to KA. Consistent with this, pretreatment with neurokinin- 1 receptors (Larson, 1988; Igwe et al., 1990a,b,c). SP selectively potentiated the CBS response to KA. The Intrathecal administration of EAAs also elicits CBS behaviors potentiation of KA effects by SP and dependence of KA (Aanonsen and Wilcox, 1986, 1987). This is of special interest behavioral sensitization on C-fiber activity suggest a pos- as Glu and Asp have been postulated to be involved in pain sible mechanism by which EAAs and SP may be involved in transmission,based on several lines of evidence: (1) Glu is colo- the mediation of pain. calized with SP in primary afferent C-fibers (De Biasi and Rus- tioni, 1988); (2) injection of formalin into the hindpaw of rats The undecapeptidesubstance P (SP) and the acidic amino acids, evokes the releaseof Glu and Asp in the dorsal spinal cord Glu and Asp are found in high concentrations in the dorsal horn (Skilling et al., 1988); (3) antagonistsof EAAs inhibit nocicep- of the spinal cord (Bessonand Chaouch, 1987), where they are tion (Cahusac et al., 1984; Aanonsen and Wilcox, 1987); and believed to act as excitatory neurotransmitters (Schneider and (4) intrathecal injections of NMDA produce an apparent hy- Perl, 1988). There are currently three major excitatory amino peralgesiceffect (Aanonsen and Wilcox, 1987). SP and EAAs also appear to interact in a reciprocal fashion in the spinal cord as SP causesthe releaseof Glu and Asp from the dorsal horn of rats (Smullin et al., 1990) and KA in turn elicits the release Received Dec. 11, 1990; revised Mar. 1, 199 1; accepted May 29, 199 1. of SP in the same system (Murray et al., 1990). While the acute This research was supported by U.S. Public Health Service Grants DA04090, effects of EAAs and SP in the spinal cord have been extensively DA04 190, and DA00 124. We gratefully acknowledge the excellent editorial as- sistance of Drs. David H. Smullin, Stephen R. Skilling, Christopher W. Murray, studied, their effects and interactions after tonic releaseor ap- and David R. Brown. plication have not been studied in the whole animal. Correspondence should be addressed to Dr. Alice A. Larson, Department of Veterinary Biology, University of Minnesota, 295 Animal Science/Veterinary Electrophysiologically, responsesto EAAs in invertebrates Medicine Building, 1988 Fitch Avenue, St. Paul, MN 55108. have been found to exhibit a profound use-dependentdecrement Copyright 0 1991 Society for Neuroscience 0270-6474/91/l 1311 l-13$05.00/0 in responsivity (Takeuchi and Takeuchi, 1964). While it was 3 1 12 Sun and Larson - Sensitization and Desensitization initially thought that vertebrate neurons failed to develop de- 90 sensitization (O’Brien and Fischbach, 1986), the use of im- A proved drug delivery systems showed that these EAA receptors do exhibit rapid desensitization. The decrease in NMDA re- ceptor responsivity appears to be calcium dependent and re- quires several seconds (Mayer and Westbrook, 1985; Zorumski et al., 1989). In contrast, desensitization to Quis and RS-(r- amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid HBr (AMPA), an agonist at the samereceptor as Quis, occurs within milliseconds and recovers within hundreds of milliseconds (Trussell et al., 1988; Tang et al., 1989). The responseto IL4 exhibits little or no desensitization (Mayer et al., 1989). While - 0.2 nmol NMDA (n.24) these studies demonstrate desensitization to specific EAA ag- 10 I I I I o-2 2-4 4-6 6-6 onists, it is unclear what the consequencesofthis desensitization 90 are in the intact animal with respect to specific physiologic ef- B fects. In light of the tendency of EAAs to desensitize,it is im- portant to determine whether the tonic releaseof EAAs or SP, such as would occur during chronic pain, might influence the intensity of the responseto a subsequentrelease of one of these neurotransmitters and thereby influence the perception of pain. 50 - If EAAs play a role in the mediation of pain, and if changes in the sensitivity to EAAs occur in thesepathways, thesechanges would provide natural regulatory (analgesicor hyperalgesic)ef- 30 - fects. The purpose of the present investigation was to study the effect of prolonged exposure of the spinal cord to the EAA I 25 pmol KA (rk20) agonistsNMDA, KA, and Quis to determine whether the be- 10 1 I I I I o-2 2-4 4-6 6-8 havioral effects produced by thesecompounds, like those of SP, 90 are altered after repeated injections. We used the paradigm of I c monitoring EAA- and SP-induced CBS behaviors to detect t changesin the sensitivity of the spinal cord to thesecompounds becauseof the easein quantifying CBS behaviors in unanes- thetized, intact mice. We then examined the effect of tonic ex- posureto one compound on the responseto the other excitatory compounds to detect changesin their interaction in the spinal cord in viva. The potential role of intemeurons in the mediation ofbehavioral sensitization or desensitizationwas then examined using antagonistsof NMDA, GABA, and glycine. 0.3 nmol Quls (k20) Materials and Methods 10 1 I I I I o-2 2-4 4-6 6-6 Animals. Male Swiss-Webster mice (20-25 gm, Biolab, White Bear Lake, MN) were housed four per cage and allowedto acclimatefor at Time (min) least24 hr prior to usein experiments.Mice wereallowed free access to food and water. Animals were used strictly in accordance with the Guidelines of the University of Minnesota Animal Care and Use Com- Figure I. Caudally directed biting and scratching responses to repeated mittee and those prepared by the Committee on Care and Use of Lab- intrathecal injections of EAAs in mice. A, Desensitization to the effect oratory Animals of the Institute of Laboratory Animal Resources, Na- of repeated injections of 0.2 nmol of NMDA. B, Sensitization to the tional Research Council [DHEW Publication (NIH) 78-23, revised 19781. effect of 25 pmol of KA. C, Sensitization to the effect of 0.3 nmol of Drug administration. All injections were made intrathecally in mice Quis. Agents were injected at 0, 2, 4, and 6 min. Behavioral responses at approximately the L5-L6 intervertebral space using a 30-gauge 0.5- were monitored for the 2-min period following each injection. Daggers inch disposable needle and a 50-~1 Luer tip Hamilton syringe after the indicate a statistically significant difference (p < 0.05) between the mean method of Hylden and Wilcox (1980).
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