Raphe Magnus Neurons Help Protect Reactions to Visceral Pain From Interruption by Cutaneous Pain

Abstract

Brink, Thaddeus S., Kevin M. Hellman, Aaron M. Lambert, and Peggy Mason. Raphe magnus neurons help protect reactions to visceral pain from interruption by cutaneous pain. J Neurophysiol 96: 3423-3432, 2006. First published August 23, 2006 doi:10.1152/jn.00793.2006. Suppression of reactions to one noxious stimulus by a spatially distant noxious stimulus is termed heterotopic antinociception. In lightly anesthetized rats, a noxious visceral stimulus, colorectal distension (CRD), suppressed motor withdrawals but not blood pressure or heart rate changes evoked by noxious hindpaw heat. Microinjection of muscimol, a GABA A receptor agonist, into raphe magnus (RM) reduced CRD-evoked suppression of withdrawals, evidence that RM neurons contribute to this heterotopic antinociception. To understand how brain stem neurons contribute to heterotopic antinociception, RM neurons were recorded during CRDelicited suppression of hindpaw withdrawals. Although subsets of RM neurons that were excited (ON cells) or inhibited (OFF cells) by noxious cutaneous stimulation were either excited or inhibited by CRD, ON cells were inhibited and OFF cells excited by an intracerebroventricularly administered opioid, evidence that the nociception-facilitating and -inhibiting functions of ON and OFF cells, respectively, are predicted by the cellular response to noxious cutaneous stimulation alone and not by the response to CRD. When recorded during CRD-elicited antinociception, RM cell discharge resembled the pattern observed in response to CRD stimulation alone. However, when hindpaw withdrawal suppression was incomplete, RM cell discharge resembled the pattern observed in response to heat alone. We propose that ON cells excited by CRD facilitate responses to CRD itself, which in turn augments excitation of OFF cells that then act to suppress cutaneous nociception. RM cells may thereby contribute to the dominance of quiet recuperative reactions evoked by potentially life-threatening visceral stimuli over transient somatomotor activity elicited by lessinjurious noxious cutaneous stimuli.

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

“…Tonic activity in an opposing cell population, ON cells, is thought to produce a state of hyperalgesia (Heinricher et al, 1989;Porreca et al, 2002). Tonic excitation of OFF cells and inhibition of ON cells in response to various opioids administered by different routes techniques are consistent, often replicated, findings in anesthetized rats (Toda, 1982;Heinricher and Rosenfeld, 1985;Barbaro et al, 1986;Fang et al, 1989;Heinricher et al, 1992Heinricher et al, , 1994Brink et al, 2006;Hellman et al, 2007). However, a single study in the unanesthetized rat did not observe any change in tonic ON cell activity in response to morphine as is observed in anesthetized rats (Martin et al, 1992).…”

Pregabalin modulation of spinal and brainstem visceral nociceptive processing

“…This may underlie spinal mechanisms of viscerosomatic convergence as well as heterotopic antinociception demonstrated by CRD-evoked suppression of cutaneous withdrawal reflexes [7].…”

Affective Brain Areas and Sleep-Disordered Breathing

“…In CCHS, the injury is substantial, extending from the anterior hypothalamus caudally through posterior regions (Figure 3A-a); in OSA, the injury is primarily in anterior regions (Figure 3B-I), but in HF, damage also extends throughout the entire rostral-caudal extent (Figure 3C-c). In all three sleep disordered conditions of OSA, HF, and CCHS, injury includes the raphé system (Woo et al 2009; Kumar et al 2011c; Kumar et al 2008b), which contains serotonergic neurons that play a significant role in pain and modulation of upper airway musculature (Brink et al 2006; Kubin et al 1992). The consequences to raphé injury in CCHS are notable in the vasculature, with exceptionally dilated basilar arteries (Kumar et al 2009d).…”