Peripheral administration of an N-methyl-D -aspartate receptor antagonist (MK-801) changes dorsal horn neuronal responses in rats Takahiro Ushida*, Toshikazu Tani, Motohiro Kawasaki, Osamu Iwatsu, Hiroshi Yamamoto Department of Orthopaedic Surgery, Kochi Medical School, Oko-cho, Nankoku, Kochi 783-8505, Japan Received 4 November 1998; accepted 23 November 1998 Abstract Due to the discovery of peripheral N-methyl-D-aspartate (NMDA) receptors, the effects of peripherally administrated MK-801, a non-competitive NMDA receptor antagonist, and phosphate buffered saline were tested by using the response changes of wide- dynamic range cells in the lumbar enlargement of the spinal cord in Sprague–Dawley rats. MK-801 (1 mM, 50 ml) administered directly into the subcutaneous tissue of the receptive field (n = 7), produces a reversible reduction of responses to noxious and innocuous stimuli by a peripheral action. There was no change in the responses to cutaneous stimuli following injection of phosphate buffered saline (n = 7) or following administration of MK-801 into the contralateral foot (n = 7). The present study suggests that MK-801 produces a local anesthetic like effect in the peripheral tissue.  1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: N-Methyl-D-aspartate-receptor antagonist; Peripheral action; Dorsal horn neuron; Analgesia; Local anesthetic; MK- 801 The N-methyl-D-aspartate (NMDA) receptor, one of three known ionotropic glutamate receptor subtypes, is widely distributed throughout the central nervous system. In the spinal cord, NMDA receptors are involved in pain transmis- sion and play a role in the expression of allodynia and hyperalgesia, abnormal pain states that develop in neuropa- thy patients and in animal models of experimental periph- eral neuropathy [7,9,10]. Recent morphological studies have revealed that glutamate receptors, including NMDA receptors, are also localized on peripheral axons and term- inals and behavioral studies have shown that these periph- eral receptors play a role in nociceptive signaling [1,3– 5,8,11,12]. MK-801 is a non-competitive NMDA receptor antagonist which binds to a site within the ion channel. MK-801 has been widely used for NMDA receptor studies within the central nervous system [6]. However, the peripheral action of MK-801 has not been studied in detail. Therefore, the aim of this study is to examine changes in the response proper- ties of wide-dynamic range neurons in the spinal dorsal horn following peripheral administration of MK-801. All experiments were approved by the Animal Experi- ment Committee of Kochi Medical School. Male Spra- gue–Dawley rats (350–450 g) were used in this study. Rats were anesthetized with intraperitoneal pentobarbital (50 mg/kg). After tracheotomy, the head and lumbar verteb- ral columns were rigidly fixed in a stereotaxic frame, and then a laminectomy (T12 to L3) was performed. Anesthesia was maintained by intravenous pentobarbital (6 mg/kg per h). Rectal temperature was maintained at 37°C by a servo- controlled heating pad. The exposed spinal cord was cov- ered with warm mineral oil to prevent drying. The lumbar enlargement was searched for a wide- dynamic range (WDR) dorsal horn cells, in segments L4- L5, near the dorsal root entry zone, to a depth of 400–1000 mm using tungsten electrodes (2–8 MQ). The cells were activated by tapping and stroking the foot as the electrode was lowered. Single-unit activity of neurons, which had Neuroscience Letters 260 (1999) 89–92 0304-3940/99/$ - see front matter  1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(98)00968-9 * Corresponding author. Tel.: +81 888 802387; fax: +81 888 802388; e-mail: ushidat@med.kochi-ms.ac.jp