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We have recently reported a model of secondary hyperalgesia in which facilitation of the thermal nociceptive tail-flick reflex following topical mustard oil is largely dependent on descending influences from the rostral ventromedial medulla (RVM). The current study was designed to examine a potential role for excitatory amino acid receptors and nitric oxide in the RVM in modulating this hyperalgesia. Topical application of mustard oil (100%) to the lateral surface of the hind leg of awake rats produced a short-lived (60 min) facilitation of the tail-flick reflex that was dose-dependently attenuated by microinjection of the selective N-methyl-d-aspartate (NMDA) receptor antagonist APV (1–100 fmol) into the RVM. Microinjection of a greater dose of APV (1000 fmol) into the RVM produced a significant inhibition of the tail-flick reflex in the presence, but not absence, of mustard oil. In contrast, microinjection of the non-NMDA receptor antagonist DNQX (10 nmol) into the RVM further enhanced the magnitude and duration of the hyperalgesic response, and produced a facilitation of the tail-flick reflex following injection into the RVM of naive animals. Similar to APV, microinjection of the nitric oxide synthase inhibitor l-NAME (100–1000 nmol) into the RVM attenuated mustard oil hyperalgesia, while the greatest dose (1000 nmol) produced a significant inhibition of the tail-flick reflex in the presence, but not absence, of mustard oil. A role for nitric oxide synthase in the RVM in mustard oil hyperalgesia was further demonstrated by a significant increase in the number of NADPH-d labeled cells in the RVM at the time of maximal hyperalgesia. Involvement of NMDA receptors and nitric oxide in the RVM in descending nociceptive facilitation was supported by the observation that microinjection of either NMDA or the NO● donor GEA 5024 into the RVM of naive animals dose-dependently facilitated the tail-flick reflex. The hyperalgesia produced by NMDA injection into the RVM was blocked by prior intra-RVM injection of either APV or l-NAME. These results support the notion that secondary hyperalgesia produced by mustard oil involves concurrent activation of dominant descending facilitatory, as well as masked inhibitory systems from the RVM. Additionally, the data suggest that descending facilitation involves activation of NMDA receptors and production NO● in the RVM, whereas inhibition involves activation of non-NMDA receptors in the RVM.