Raphe Magnus

Descending modulation by the Raphe Magnus (RM) plays a critical role in homeostasis and pain control. Descending pathways from the brainstem to the spinal cord alter incoming somatosensory messages at the first central locus within the superficial dorsal horn. The descending pain modulatory system is remarkably powerful. Stimulation of the descending modulatory system alone is sufficient to block purposeful escape from, as well as reflexive reactions to, profoundly noxious insults like a surgical laparotomy (Reynolds, 1969), and is utilized as treatment for severe intractable pain (Akil et al., 1978). The periaqueductal gray (PAG) is the starting point of the canonical descending pain modulatory pathway, and the primary target of PAG neurons is RM. RM neurons, in turn, directly project to and modify the responses of dorsal horn neurons to somatosensory stimulation. Activation of RM neurons produces robust inhibition of lamina I dorsal horn neurons (Fields et al. 1977) and, consequently, analgesia (Fardin et al., 1984). Decades of work have led to the consensus view that the descending PAG-to-RM-to-dorsal horn pathway produces analgesia by inhibiting incoming sensory signals.

This sensory inhibition blunts pain affect, as exhibited by loss of organized escape behavior in rats following a noxious stimulation (Fardin et al., 1984). Clinically, this also underlies the efficacy of opioid agonists, which primarily affect sensory pain suppression and secondarily, attenuate affective pain reactions by engaging the PAG-to-RM-to-dorsal horn modulation.

Teleologically, RM’s relevance to pain modulation could be viewed as a natural offshoot of its central role in protecting homeostasis. While inactivation of RM does not block acute pain (Mitchell et al., 1998), it does abolish pain-induced cardiovascular effect (Gau et al., 2009). These findings posit a role for RM activity in facilitating pain via sympathetic synapses. In addition, this observation points out the logic of characterizing sympathetic outflow as a practical and accessible surrogate for human RM function. Animal RM is similar to human RM because pain (Dubé et al., 2009) and sympathetic activity (Macefield and Henderson, 2010) are correlated with increased BOLD signals in the region containing RM in humans. Interestingly, it was also noted that there is reduced echogenecity of RM in Parkinson patients with overactive bladders compared to Parkinson patients without bladder symptoms (Walter et al., 2006)

Plausibly, one could hypothesize that some neurons in RM play a role in pain while other play a role in homeostasis. This does not appear to be the case because RM pain inhibitory neurons increase parasympathetic activity as measured by Heart Rate Variability (HRV) (Hellman et al., 2009). Additionally, we have demonstrated that pain facilitator neurons in RM, or ON cells, are inhibited during micturition, and the reverse is true for pain inhibitory neurons, or OFF cells (Baez et al., 2005). Consistent with this idea, analgesia to cutaneous pain is observed in rats during micturition when RM pain inhibitory neurons are firing (Baez et al., 2005). In summary, these findings imply that pain facilitator cells elicit sympathetic activity, and conditions with excessive pain facilitation would be associated with excess sympathetic activity. Conversely, pain inhibitory cells drive parasympathetic activity. Therefore, conditions with impairments in pain inhibition in RM would be associated with decreased parasympathetic activity. Particularly, under the background of pain during micturition, when pain inhibitory cells should be active, patients with Interstitial Cystitis (IC) may demonstrate a lack of heart rate variability, increased heart rate, and increased blood pressure. The next step would be to confirm that RM inactivation abolishes pain behavior in animal models of bladder pain. This is highly likely, as RM inactivation has reduced pain in over 10 different types of chronic pain in animal models (Reviewed in Porreca et al., 2002).

Comments