Nociceptive facilitating neurons in the rostral ventromedial medulla

Abstract

The role of the periaqueductal gray-rostral ventromedial medulla (RVM) system in descending inhibition of nociception has been studied for over 30 years. The neural basis for this antinociceptive action is reasonably well understood, with strong evidence that activation of a class of RVM neurons termed 'off-cells' exerts a net inhibitory effect on nociception. However, it has recently become clear that this system can facilitate, as well as inhibit pain. Although the mechanisms underlying the facilitation of nociception have not been conclusively identified, indirect evidence points to activation of a class of neurons termed 'on-cells' as mediating descending facilitation. Here we used focal infusion of the tridecapeptide neurotensin within the RVM in lightly anesthetized rats to activate on-cells selectively. Neurotensin has been shown in awake animals to produce a dose-related, bi-directional effect on nociception when applied within the RVM, with hyperalgesia at low doses, and analgesia at higher doses. Using a combination of single cell recording and behavioral testing, we now show that on-cells are activated selectively by low-dose neurotensin, and that the activation of on-cells by neurotensin results in enhanced nociceptive responding, as measured by the paw withdrawal reflex. Furthermore, higher neurotensin doses recruit off-cells in addition to on-cells, producing behavioral antinociception. Selective activation of on-cells is thus sufficient to produce hyperalgesia, confirming the role of these neurons in facilitating nociception. Activation of on-cells likely contributes to enhanced sensitivity to noxious stimulation or reduced sensitivity to analgesic drugs in a variety of conditions.

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

“…The relative recruitment of these neurons can alter under different conditions and circumstances such that spinal sensory transmission may be potentiated or suppressed. 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.…”

NK-1 Receptors Modulate the Excitability of on Cells in the Rostral Ventromedial Medulla

“…For example, injection of neurotensin or cholecytokinin into the RVM decreased paw withdrawal latency and activated ON cells in a dose-specific manner (Heinricher and Neubert 2004;Neubert et al 2004) whereas activation of OFF cells produces antinociception (Heinricher et al 1994;Heinricher and Tortorici 1994;Neubert et al 2004). Response characteristics of NEUTRAL cells also change over the course of inflammation whereby they can develop response properties similar to ON or OFF cells (Miki et al 2002).…”

Nociceptin/orphanin FQ blocks the antinociception induced by mu, kappa and delta opioid agonists on the cold water tail-flick test

“…Recent studies (Heinricher, 2005;Neubert et al, 2004) have shown that the actual effect of N/OFQ depends on which neurons have been activated, off-cell or on-cell (pain-inhibiting neuron and pain-facilitating) when the peptide is given. OFQ inhibited the function of both cells (Heinricher et al, 1997;Mogil and Paternak, 2001).…”