RAPID COMMUNICATION a2-Adrenoceptors Modulate NMDA-Evoked Responses of Neurons in Superficial and Deeper Dorsal Horn of the Medulla

Kai-Ming Zhang, Xiao-Min Wang, Angela M. Peterson, Wenride (clonidine) , an a2-adrenoceptor (a2AR) agonist, is reYan Chen, and Sukhbir S. Mokha. a2-Adrenoceptors modulate ported to be effective in treating neuropathic pain in humans NMDA-evoked responses of neurons in the superficial and deeper (Eisenach et al.1995; Tamsen and Gordh 1984) and in attendorsal horn of the medulla. J. Neurophysiol. 80: 2210–2214, 1998. uating hyperalgesia induced by nerve injury or inflammation Extracellular single unit recordings were made from neurons in in animal studies (Kayser et al. 1995; Post et al. 1987; Puke the superficial and deeper dorsal horn of the medulla ( trigeminal et al.1994; Solomon et al. 1989; Xu et al. 1992). Autoradionucleus caudalis) in 21 male rats anesthetized with urethan. NMDA graphic studies demonstrated the presence of a2ARs in the produced an antagonist-reversible excitation of 46 nociceptive as dorsal horn, particularly in the superficial dorsal horn of the well as nonnociceptive neurons. Microiontophoretic application of spinal cord (Roudet et al. 1994; Unnerstall et al. 1984; Sullia preferential a2-adrenoceptor (a2AR) agonist, (2-[2,6-dichloroaniline]-2-imidazoline) hydrochloride (clonidine) , reduced the van et al. 1987) and the medulla (Unnerstall et al. 1984). NMDA-evoked responses of 86% (6/7) of nociceptive-specific Microiontophoretically applied norepinephrine (NE) is re(NS) neurons, 82% (9/11) of wide dynamic range (WDR) neuported to selectively inhibit nociceptive responses of deep rons, and 67% (4/6) of low-threshold (LT) neurons in the superfidorsal horn neurons (Belcher et al. 1978; Fleetwood-Walker cial dorsal horn. In the deeper dorsal horn, clonidine inhibited the et al. 1985; Headley et al. 1978; reviewed in Jones 1991). NMDA-evoked responses of 94% (16/17) of NS and WDR neuConsistent with data from behavioral studies (reviewed in rons and 60% (3/5) of LT neurons. Clonidine facilitated the Jones 1991), the selective inhibitory effect of NE was sugNMDA-evoked responses in 14% (1/17) of NS, 9% (1/11) of gested to involve a2ARs (Davies and Quinlan 1985; FleetWDR, and 33% (2/6) of LT neurons in the superficial dorsal horn. wood-Walker et al. 1985). However, NE was also reported Idazoxan, an a2AR antagonist, reversed the inhibitory effect of to produce nonselective inhibitory modulation of primate clonidine in 90% (9/10) of neurons, whereas prazosin, an a1adrenoceptor antagonist with affinity for a2BAR, and a2CAR, were spinothalamic tract neurons (Willcockson et al. 1984) and ineffective. We suggest that activation of a2ARs produces a preinterneurons in the superficial dorsal horn of the spinal cord dominantly inhibitory modulation of the NMDA-evoked responses in the rat (Howe and Zieglgänsberger 1987; Todd and Millar of nociceptive neurons in the medullary dorsal horn. 1983). Although behavioral studies in mice indicated the importance of adrenoceptors in modulating biting and scratching behavior induced by intrathecal NMDA (AaI N T R O D U C T I O N nonsen and Wilcox 1987), no previous electrophysiological studies investigated the role of a2-noradrenergic receptors in The dorsal horn of the medulla ( trigeminal nucleus caumodulating the NMDA-evoked responses of physiologically dalis) is an important relay for nociceptive and thermosencharacterized nociceptive neurons in the brain. This study sory information from the orofacial region (reviewed in was therefore designed to investigate the a2AR-mediated Light 1992; Sessle 1987). Glutamate, a putative excitatory modulation of NMDA-evoked responses of neurons in the neurotransmitter (Watkins and Evans 1981), is present in superficial and deeper dorsal horn of the medulla. trigeminal primary afferent fibers (Clements and Beitz 1991). Glutamate produces its actions by acting on modulate N-methyl-D-aspartic acid (NMDA), non-NMDA ionotropic M E T H O D S [({)-a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic This study was based on data obtained from 21 male Spragueacid (AMPA)/Kainate] , and metabotropic receptors in the Dawley rats (230–360 g) anesthetized with urethan (1.5 g/kg ip) . spinal cord. The superficial dorsal horn of the medulla conMethods for animal preparation, monitoring the level of anesthesia, tains high densities of NMDA (Tallaksen-Greene et al. neuronal recording, and characterization of trigeminal neurons 1992) and non-NMDA ionotropic (Kondo et al. 1995; Talwere similar to those described previously (Mokha 1992, 1993; laksen-Greene et al. 1992) and metabotropic (TallaksenZhang et al. 1996). The rat’s face was carefully shaved for adeGreene et al. 1992) receptors. NMDA receptors are involved quate stimulation and mapping of receptive fields. To improve the in mediating nociceptive neurotransmission and neuroplasstability of extracellular recordings from the superficial dorsal horn ticity (hyperalgesia) in the dorsal horn (reviewed in Wilcox of the medulla, a small metallic brass plate was fixed to the skull, 1993). (2-[2,6-Dichloroaniline]-2-imidazoline) hydrochloand the head was ventroflexed. The dorsal surface of the medulla was exposed and covered with warm agar (3–4% agar in normal saline at 407C). All protocols were approved by the Institutional The costs of publication of this article were defrayed in part by the Animal Care and Use Committee of Meharry Medical College. payment of page charges. The article must therefore be hereby marked Recordings were made with the central barrel (2 M NaCl or 2% ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. pontamine sky blue in 0.5 M sodium acetate) of a seven-barrel