Descending controls Flashcards
How does mPFC play a role in regulating nociception?
mPFC is thought to exert descending inhibitory control. Cheriyan and Sheets (2018) showed that mPFC neurons projecting to the PAG exhibited reduced excitability in an animal model of nerve injury pain. This finding could support the concept of dysfunction in descending control in pathological pain states, with reduced “top-down” recruitment of descending inhibition from the PAG.
Zhuo et al., 2000
In 2000, Zhuo and Colleagues have also shown that stimulation of the ACC results in a pronociceptive effect which was relayed through the RVM. As a result the ACC is thought to exert descending facilitation.
Is there a facilitatory influence that is not mediated by RVM?
There is also evidence for a facilitatory influence that is not mediated by the RVM, possibly involving a direct projection from ACC to the spinal cord. This RVM-independent facilitation produces an enhancement of synaptic transmission and increased expression of c-fos in laminae III through V (Chen et al., 2018). However, the behavioral relevance of this projection has not yet been documented.
How does stress-induced analgesia work?
The phenomenon of “stress-induced analgesia,” in which a severe and immediate threat inhibits pain sensation despite significant injury has been well documented (Butler and Finn, 2009).
Although stress-induced analgesia can take a number of forms, at least in some cases, it appears to be mediated through recruitment of RVM OFF-cells via opioid-dependent mechanisms in the basolateral amygdala (Helmstetter, 1992). In contrast with intense stress and fear, mild stress can exacerbate pain. This “stress-induced hyperalgesia” is mediated by RVM ON-cells recruited via the dorsomedial nucleus of the hypothalamus (Wagner et al., 2013).
What role does parabrachial input to the RVM play in persistent inflammation?
The PB input to RVM may play an important role in the transition from acute to persistent pain. Under basal conditions or in acute inflammation, blocking PB contralateral to a stimulated paw interferes with the OFF-cell pause and ON-cell burst evoked by that stimulation, and has a hypoalgesic effect. At later time points/during persistent inflammation, blocking PB contralateral to an inflamed paw does not reliably interfere with OFF- and ON-cell responses, and has no effect on nociceptive behavior. Instead, blocking PB ipsilateral to the site of inflammation prevents the OFF-cell pause and ON-cell burst evoked by stimulation of the inflamed paw, and reverses hyperalgesia (Chen et al., 2019). PB ipsilateral to the inflamed paw thus conveys nociceptive information to RVM during persistent inflammation, maintaining the hypersensitivity of ON- and OFF-cells to innocuous stimuli. These findings indicate that the PB ipsilateral to an inflamed site has the capacity to provide nociception-related input to RVM ON- and OFF-cells, but that this input is only recruited or unmasked in persistent inflammation
Harper et al., 2018
Dysfunction in descending models is likely to contribute to significant chronic pain. Indeed, functional imaging studies are providing increasing evidence that functional connectivity with descending control systems, most notably the PAG, is depressed in chronic pain states (Harper et al., 2018)
Why is understanding the role of RVM in persistent pain complicated?
Understanding the role of the RVM in persistent pain has necessarily been complicated by the fact that increased pain or lowered pain threshold could reflect an increase in ON-cell activity, a decrease in OFF-cell output, or, and most likely, a combination of these two factors
Why is thought that persistent pain states are, at least in part, a reflectio of dysfunction in descending control systems?
The dysfunction in descending control systems is well documented using the “conditioned pain modulation” (CPM) paradigm, in which a painful stimulus delivered to one part of the body suppresses the pain resulting from a standardized noxious stimulus applied at a remote site. An impaired ability to mount a CPM response is a frequent characteristic of patient populations with chronic pain (Lewis et al., 2012).
Does RVM truly modulation perception of pain or does it simply control output of nocifensor reflex circuits?
Multiple lines of evidence argue against this latter view. First, although RVM terminals are not limited to the dorsal horn, projections of OFF- and ON-cells to the dorsal horn have been identified, including interactions with primary afferent terminals (Zhang et al., 2015). Second, activity of RVM neurons is well correlated with activity of dorsal horn nociceptive neurons, and less strongly linked to motor output (Salas et al., 2016). Third, manipulations of RVM can be demonstrated to modulate the affective dimension of pain, and not simply spinal reflexes (Gomtsian et al., 2018). Viewed as a whole, these data strongly support the idea that the brainstem descending control system modulates nociception as a sensory system.
Why is it a challenge to analyse the RVM circuitry properly?
An important challenge to analysis of RVM circuitry has been the difficulty of applying genetic tools to the two cell classes, since neither OFF-cells nor ON-cells, as a class, express a specific neurotransmitter. Over half of both the OFF- and ON-cell classes are GABAergic, implying that function derives from connectivity rather than cell “type”. Indeed, it is likely that GABAergic ON-cells facilitate nociception by inhibiting GABA-mediated circuits at the level of the dorsal horn (Francois et al., 2017). There is also recent evidence suggesting that co-localization of enkephalin with GABA might be a marker for OFF-cells, since specific activation of RVM GABA+enkephalin neurons produced antinociception (Zhang et al., 2015). Verifying this possibility will require significant additional analysis. This is because, as already noted, co-activation of ON-cells and OFF-cells produces antinociception, thus the possibility that some GABA+enkephalin neurons are ON-cells cannot be ruled out.
Is 5-HT a key neurotransmitter in descending facilitation?
5-HT is the neurotransmitter of the major projection from the RVM to the spinal cord.
Kim et al., (2014) found that in a neuropathic pain model, extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. They also showed that the central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem and that central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia.
A candidate molecular link between 5-HT3AR and its downstream effector TRPV1 is PKC since it can be activated by 5-HT3AR and phosphorylation of TRPV1 by PKC leads to potentiation of TRPV1 activity (Vay et al., 2012).
Is descending facilatation mediated through activation of 5HT3 receptors?
In vivo electrophysiological methods, have demonstrated a pro-nociceptive function for spinal 5-HT3 receptors on spinal neuronal activity since topical spinal application of the selective antagonist ondansetron significantly reduced spinal neuronal activity in normal and pathaphysiological conditions (Suzuki et al., 2004)
How do genetic studies show that 5HT3R is essential for descending facilitation?
Substantiating the role of 5-HT3Rs in pain maintenance further, KO mice lacking the A subunit of the 5-HT3R, which is required for functionality of the receptor, have been shown to display normal acute pain-like responses, but attenuated ongoing hypersensitivity produced by formalin-induced inflammation (Zeitz et al., 2002). Taken together, these results show that 5-HT facilitates persistent pain-like states via activation of 5-HT3Rs most likely due to an increased descending serotonergic drive from higher centres in the brain and in particular, the rostral ventromedial medulla (RVM)
Do other decending inhibitory pathways exist outside of the RVM?
NA pathway (has a powerful analgesic effect on dorsal horn through activation of alpa2R) and the Diffuse noxious inhibitory control (DNIC)
DNIC requires the dorsal reticularis nucleus (DRt) and interacts with WDR in the dorsal horn.
