Activation of brainstem N-methyl-D-aspartate receptors is required for the analgesic actions of morphine given systemically

Abstract

The analgesic actions of opioids are in large part mediated by activation of brainstem pain modulating neurons that depress nociceptive transmission at the level of the dorsal horn. The present study was designed to characterize the contribution of N-methyl-D-aspartate (NMDA)- and non-NMDA-mediated excitatory transmission within the rostral ventromedial medulla (RVM) to the activation of brainstem inhibitory output neurons and analgesia produced by systemic morphine administration. The NMDA receptor antagonist D-2-amino-5-phosophonopentanoic acid (AP5), the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) or saline was infused into the RVM of lightly anesthetized rats while recording the activity of identified pain modulating neurons: 'off-cells', thought to inhibit nociceptive transmission, and 'on-cells', thought to facilitate nociception. Nociceptive responsiveness (tail flick latency) was not affected by either antagonist. AP5, but not CNQX, attenuated or blocked activation and disinhibition of off-cells and the antinociception produced by systemically administered morphine. Reflex-related discharge of on-cells was unaffected by AP5, but significantly attenuated by CNQX. The present results highlight two important aspects of RVM pain modulatory circuits. First, morphine given systemically produces its analgesic effect at least in part by recruiting an NMDA-mediated excitatory process to activate off-cells within the RVM. This excitatory process may play a role in the analgesic synergy produced by simultaneous mu-opioid activation at different levels of the neuraxis. Second, reflex-related activation of on-cells is mediated by a non-NMDA receptor, and this activation does not appear to play a significant role in regulating reflex responses to acute noxious stimuli. Excitatory amino acid-mediated excitation thus has at least two distinct roles within the RVM, activating off-cells and on-cells under different conditions.

NMDA receptor-mediated activation of medullary pro-nociceptive neurons is required for secondary thermal hyperalgesia

“…Under basal conditions, there appears to be no significant excitatory amino acid-mediated synaptic input to off-cells or neutral cells, whereas the reflex-related on-cell burst is mediated by a non-NMDA receptor (Heinricher and Roychowdhury, 1997;Heinricher et al, 2001b). Consistent with this, we saw no effect of AP5 or CNQX, or of the broad-spectrum excitatory amino acid antagonist kynurenate microinjection on paw withdrawal or tail flick latency in control animals in this or previous work (Heinricher and McGaraughty, 1998;Heinricher et al, 1999Heinricher et al, ,2001b.…”

Lateral hypothalamic-induced antinociception may be mediated by a substance P connection with the rostral ventromedial medulla

“…Support for this hypothesis comes from studies that identify neurons in the RVM that both activate and inhibit nociception in the dorsal horn Heinricher et al, 2001;Heinricher et al, 1999). For example, neurons have been identified in the RVM that are immunoreactive for glutamate decarboxylase and inhibit nociception (Winkler et al, 2006).…”

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

“…The neural basis for this bidirectional modulation has long been established 12 : the On cells burst-fire in response to peripheral noxious stimuli, enhance nociception and are implicated in the hypersensitivities associated with a range of pain states, [13][14][15] whereas Off cells undergo a pause in firing in response to peripheral noxious stimuli and are involved in inhibiting spinal neuronal activity. 16,17 The responses of these RVM neurons to noxious stimuli are inversely predictive of their responses to systemic or local opioid administration 12,18 ; hence, On cells are inhibited by morphine, but Off cells are (indirectly) activated.…”