Activation of Serotonergic Neurons in the Raphe Magnus Is Not Necessary for Morphine Analgesia

Abstract

A wealth of pharmacological and behavioral data suggests that spinally projecting serotonergic cells mediate opioid analgesia. A population of medullary neurons, located within raphe magnus (RM) and the neighboring reticular nuclei, contains serotonin and is the source of serotonin in the spinal dorsal horn. To test whether serotonergic neurons mediate opioid analgesia, morphine was administered during recordings from medullary cells that were physiologically characterized as serotonergic (5HTp) by their slow and steady discharge pattern in the lightly anesthetized rat. Selected 5HTp cells (n = 14) were intracellularly labeled, and all contained serotonin immunoreactivity. The discharge of most 5HTp cells was not affected by an analgesic dose of systemic morphine. In a minority of cases, 5HTp cells either increased or decreased their discharge after morphine administration. However, morphine altered the discharge of some 5HTp cells in the absence of producing analgesia and conversely did not alter the discharge of most 5HTp cells in cases in which analgesia occurred. RM cells with irregular discharge patterns and excitatory or inhibitory responses to noxious tail heat were classified as ON and OFF cells, respectively. All ON and OFF cells that were intracellularly labeled (n = 9) lacked serotonin immunoreactivity. All ON cells were inhibited, and most OFF cells were excited by systemic morphine. Because 5HTp cells do not consistently change their discharge during morphine analgesia, they are unlikely to mediate the analgesic effects of morphine. Instead, nonserotonergic cells are likely to mediate morphine analgesia in the anesthetized rat. In light of the sensitivity of morphine analgesia to manipulations of serotonin, serotonin release, although neither necessary nor sufficient for opioid analgesia, is proposed to facilitate the analgesic effects of nonserotonergic RM terminals in the spinal cord.

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

“…Since state changes alter the tonic firing of ON and OFF cells (Leung and Mason, 1999), the behavioral state changes evoked by morphine may have secondarily altered the tonic discharge of RM ON and OFF cells. The anesthetized state is not uniform, and state changes during general anesthesia influence the tonic discharge of rat ON and OFF cells (Grahn and Heller, 1989;Leung and Mason, 1995;Jinks et al, 2004); this may account for the changes in ON and OFF cell activity elicited by morphine in the anesthetized rat (Gao et al, 1998;Hellman et al, 2007). In sum, our data suggest that the tonic discharge of ON and OFF cells does not mediate antinociception.…”

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

“…40,41 This hypothesis, however, contradicts cellular recordings from nucleus raphe magnus neurons, which show that activation of 5-HT-containing neurons is not necessary for morphine analgesia. 42,43 Notwithstanding the increased concentration of 5-HT metabolites in spinal and supraspinal areas consequent to systemic morphine injection, 44,45 and observations that 5-HT receptor antagonists can modulate morphine analgesia, 41 it could be that morphine affects other processes that are under the direction of the RVM, such as behavioral state, which may themselves alter central serotonergic tone. Thus, any morphine-evoked increases in 5-HT release may be secondary to primary opioid effects.…”

“…Thus, any morphine-evoked increases in 5-HT release may be secondary to primary opioid effects. 42 The 5-HT 1 receptors have been implicated in the inhibitory effects of 5-HT, and accordingly, 5-HT 1B/1D receptors are targets for agonist agents that treat migraine. 46 With respect to noncranial pains, the antinociceptive actions of brainstem 5-HT are largely mediated by spinal 5-HT 1A receptors.…”

Roles for Pain Modulatory Cells during Micturition and Continence

“…Medullary modulation of nociceptive transmission is nonserotonergic (Aimone and Gebhart, 1986;Matos et al, 1992;Sorkin et al, 1993;Gao et al, 1997Gao et al, , 1998, mediated by two nonserotonergic VMM cell types (Fields et al, 1983;Barbaro et al, 1986;Mason, 1997;Gao and Mason, 2000). OFF cells are inhibited by noxious cutaneous stimulation, are excited by opioids, and are thought to suppress cutaneous nociceptive transmission, whereas ON cells are excited by noxious cutaneous stimulation, inhibited by opioids, and likely facilitate cutaneous nociceptive transmission.…”