Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla

Abstract

Neurons in the rostral ventromedial medulla (RVM) are the major source of serotonergic projections to the dorsal horn. A large body of evidence implicates RVM serotonergic neurons in the modulation of spinal nociceptive transmission. Three physiological classes of RVM neurons, on, off, and neutral cells, are postulated to have different nociceptive modulatory effects on spinal nocifensor reflexes. This study was undertaken to determine which RVM cell class(es) contains 5- HT. In anesthetized rats, RVM neurons were identified by their responses to noxious cutaneous stimuli, intracellularly labeled, and processed for 5-HT immunocytochemistry. Labeled neurons were examined with epifluorescence and imaged using a confocal laser microscope. A total of 25 RVM neurons were intracellularly labeled. No off (n = 9) or on (n = 8) cells were serotonergic. Half of the neutral cells (4 of 8) demonstrated 5-HT immunoreactivity. These results call for a reevaluation of the mechanisms of RVM modulatory influence on spinal cord nociceptive transmission. The finding that some neutral cells are serotonergic strongly suggests that serotonergic neutral cells are involved in the modulation of spinal nociceptive transmission. Additionally, inhibition of spinal nociceptive transmission by off cells is unlikely to involve 5-HT release. Finally, since opioid administration does not alter the firing of RVM neutral cells, the results of the present study indicate that serotonergic RVM neurons do not directly mediate the effects of supraspinal opioids in the rat.

Central modulation of pain

“…Together, such studies led to the reason-able assumption that the RVM provided descending serotonergic pain modulation from the RVM. However, attempts to determine whether either the on-cells or off-cells of the RVM are serotonergic led to the realization that other, nonserotonergic neurons from the RVM may modulate pain (73). In a study of 25 identified RVM neurons, none of the on-cells (i.e., 8 neurons) or off-cells (i.e., 9 neurons) expressed 5-HT, and only 4 out of 8 neutral cells were labeled with 5-HT (73).…”

“…However, attempts to determine whether either the on-cells or off-cells of the RVM are serotonergic led to the realization that other, nonserotonergic neurons from the RVM may modulate pain (73). In a study of 25 identified RVM neurons, none of the on-cells (i.e., 8 neurons) or off-cells (i.e., 9 neurons) expressed 5-HT, and only 4 out of 8 neutral cells were labeled with 5-HT (73). Moreover, only 20% of RVM neurons were found to be serotonergic (74), and most of the spinal projections from the RVM are either glycinergic or GABAergic.…”

Discharge of Raphe Magnus on and offCells Is Predictive of the Motor Facilitation Evoked by Repeated Laser Stimulation

“…OFF cells are inhibited by noxious stimulation and excited by opioids, whereas ON cells are excited by noxious stimulation and inhibited by opioids. Both cell types are nonserotonergic (Potrebic et al, 1994;Mason, 1997;Gao and Mason, 2000).…”

Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits

“…Electrophysiological classification of RVM neurons into so-called "on" (i.e., pain facilitatory) and "off" (pain inhibitory) cell groups surprisingly did not include 5HT neurons (Potrebic et al, 1994;Mason, 1997;Gao and Mason, 2000). Rather, serotonergic neurons constitute a heterogeneous population, with slow, regular discharge patterns and variable responses to noxious stimuli and to opioid agonists (Gao and Mason, 2001;Zhang et al, 2006).…”

“…Comparable conclusions were made from studies in the rat (Porreca et al, 2002;Suzuki et al, 2004b). For example, although intrathecal injection of relatively non-selective 5HT receptor antagonists reduces the analgesia induced by chemical or electrical stimulation of the RVM (Hammond and Yaksh, 1984;Jensen and Yaksh, 1984;Barbaro et al, 1985), studies using more selective antagonists demonstrated that descending 5HT systems can exert both inhibitory or facilitatory actions on nociceptive processing via the 5HT1A and 1B/D receptors or the 5HT1A, 2A, and 3 receptors, respectively (Green et al, 2000;Zeitz et al, 2002;Sasaki et al, 2006).Electrophysiological classification of RVM neurons into so-called "on" (i.e., pain facilitatory) and "off" (pain inhibitory) cell groups surprisingly did not include 5HT neurons (Potrebic et al, 1994;Mason, 1997;Gao and Mason, 2000). Rather, serotonergic neurons constitute a heterogeneous population, with slow, regular discharge patterns and variable responses to noxious stimuli and to opioid agonists (Gao and Mason, 2001;Zhang et al, 2006).…”