Noradrenergic input to nociceptive modulatory neurons in the rat rostral ventromedial medulla

Abstract

Within the rostral ventromedial medulla (RVM), there are two classes of putative pain modulation neurons: ON cells and OFF cells, which respectively burst or pause prior to withdrawal reflexes elicited by noxious stimulation. Alpha-adrenergic agonists injected into the RVM produce changes in the latency of spinal nocifensive reflexes and, when iontophoretically applied, alter the firing of RVM ON but not OFF cells. To provide further information about the contribution of norepinephrine to RVM neuron function, we analyzed the distribution of tyrosine hydroxylase immunoreactive (TH-ir) appositions upon RVM ON and OFF cells. In the lightly anesthetized rat, seven ON and five OFF cells were identified by changes in their discharge rate in relation to nociceptive withdrawal reflexes and were labeled by intracellular injection of neurobiotin. Sections containing labeled cells were visualized by using avidin conjugated to a Texas Red fluorophore. Tissue with labeled cells was subsequently processed for TH-ir by using a Bodipy fluorophore conjugated secondary antibody. The distribution of the Bodipy-labeled fibers and terminals upon the Texas Red-labeled neurons was mapped using a confocal laser-scanning microscope. All the labeled neurons exhibited close TH-ir appositions. Appositions were of two types: swellings and fibers. Although the numbers and density of appositions varied among the cells, there were no consistent differences that correlated with physiological properties. Thus the overall density of appositions for ON cells (29.0 +/- 22.2 x 10(4) microns2) did not differ significantly from that for OFF cells (25.4 +/- 22.2 x 10(4) microns2). Tyrosine hydroxylase immunoreactive (TH-ir) appositions upon ON and OFF cells varied with their location along the dorso-ventral axis with more ventral neurons having a greater density of TH-ir swelling-type appositions. In a separate study, TH-ir and dopamine-beta-hydroxylase-like immunoreactivity (DBH-ir) were mapped in the same sections by using confocal microscopy. Nearly 97% of the TH-ir profiles co-localized with DBH-ir. These observations provide evidence that both ON and OFF cells in the RVM are targeted by noradrenergic inputs.

Roles of α1- and α2-Adrenoceptors in the Nucleus Raphe Magnus in Opioid Analgesia and Opioid Abstinence-Induced Hyperalgesia

“…Our previous studies have shown that excitation of RVM Offcells, or primary cells identified in vitro, mediates the analgesia induced by PAG DAMGO, consistent with their proposed inhibitory action on spinal pain transmission (Pan et al, 1997;Fields and Basbaum, 1999). Furthermore, we have demonstrated anatomically that Off-cells receive a dense noradrenergic input (Meng et al, 1997). The current finding that blockade of ␣ 1receptors by prazosin considerably attenuates PAG DAMGOinduced analgesia indicates that activation of noradrenergic synaptic inputs acting on ␣ 1 -receptors directly excites NRM primary cells (Off-cells) and is required for the antinociceptive effect of PAG opioids (Fig.…”

“…Increasing evidence suggests that activation of these -expressing medullary cells accounts at least partially for the increased pain sensitivity, or hyperalgesia, during opioid withdrawal and in other chronic pain states (Bederson et al, 1990;Kaplan and Fields, 1991;Pan et al, 2000;Porreca et al, 2001Porreca et al, , 2002. These cells also receive a dense NA input (Meng et al, 1997). Our observation that ␣ 1 -receptor blockade attenuates opioid withdrawal-induced hyperalgesia indicates that noradrenergic inputs excite NRM secondary cells through ␣ 1 -receptors and that this excitation of secondary cells is required for the hyperalgesia during opioid withdrawal (Fig.…”

“…Noradrenergic neurons in the A5 and A7 cell groups also modulate spinal pain transmission through their direct spinal projections (Burnett and Gebhart, 1991;Nuseir and Proudfit, 2000). The RVM does not contain noradrenergic cells (Basbaum, 1992) but receives a dense noradrenergic projection from the A5 and A7 neurons (Tanaka et al, 1996;Meng et al, 1997). These noradrenergic inputs have been demonstrated to affect pain modulation by RVM neurons (Haws et al, 1990;Nuseir et al, 1999).…”

The noradrenergic locus coeruleus as a chronic pain generator

“…This implies that pronociceptive effects would originate from neurons localized more dorsally in the LC. By contrast, both inhibitory and facilitatory effects of the RVM, another structure responsible for the bidirectional modulation of pain, are thought to be mediated by interspersed bulbospinal projections from pain‐inhibitory (OFF‐cell) and excitatory (ON‐cell) projection neurons that both receive direct noradrenergic innervation (Meng et al, ; Porreca et al, ; Suzuki et al, ; Heinricher, et al, ).…”

Characterization of neurotensin's bipolar effects on nociceptive modulation using SR 142948A and SR 48692, two non-peptide neurotensin receptor antagonists

“…Norepinephrine has also been shown to play a role in nociceptive modulation at the level of the RVM. Both "on-" and "off-cells" have been demonstrated to be targets of descending noradrenergic projection neurons (Meng et al, 1997). Moreover, both facilitatory and inhibitory effects on nociception have been demonstrated for noradrenergic compounds within the RVM, and appear to involve different receptor subtypes.…”