ReviewDescending control of nociception: Specificity, recruitment and plasticity
Introduction
The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for the regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Supraspinal (or descending) control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. Initial reports in the 1970's and 1980's were of inhibitory influences from sites in the midbrain periaqueductal gray (PAG) and from the midline nucleus raphe magnus and adjacent reticular regions in the pons and medulla, the rostral ventromedial medulla (RVM, see Fields et al., 2006, Heinricher and Ingram, 2008 for recent reviews). For many decades attention focused on these areas as sources of descending inhibitory control, with a role in endogenous analgesia (antinociception) in states of extreme stress(Bolles and Fanselow, 1980, Terman et al., 1984) or in creating contrast in sensory signals that sharpened the signalling of pain by ascending pathways (Le Bars, 2002).
It is now evident that descending control can be facilitatory as well as inhibitory. Indeed, facilitatory and inhibitory influences on spinal events are often reported to emanate from a single brain region (e.g., Zhuo and Gebhart, 1997)]. Some descending influences are tonically active, but the balance between inhibition and facilitation is dynamic, and can be altered in different behavioral, emotional and pathological states. As already noted, it has long been recognized that intense stress and fear are associated with hypoalgesia (a decreased responsiveness to noxious stimuli) that reflects a shift towards descending inhibition. By contrast, inflammation and nerve injury, sickness, and chronic opioid administration are associated with hyperalgesia (an increased responsiveness to noxious stimuli) that in part reflects a shift towards descending facilitation. Of clinical importance, there is much evidence to suggest that descending facilitation of spinal nociception is a major contributor to central sensitization and the development of secondary hyperalgesia, indicating that the balance shifts in favor of facilitation in the transition from acute to chronic pain.
Descending control arises from a number of supraspinal sites, but the best studied is the PAG-RVM system mentioned above (Fig. 1). The PAG is heavily interconnected with the hypothalamus and limbic forebrain structures including the amygdala, and also receives direct spinomesencephalic input. The PAG projects to the RVM, which in turn sends its output to dorsal horn laminae important in nociceptive function. This system has a pivotal role in organizing strategies for coping with intrinsic and extrinsic stressors, and is also recognized as the central site of action of analgesic agents including opioids, cyclooxygenase inhibitors, and cannabinoids (Hohmann et al., 2005, Leith et al., 2007, Yaksh et al., 1976). Understanding the PAG-RVM system is thus of considerable importance from both a behavioral and therapeutic point of view. Spinal mechanisms that mediate descending control from the PAG are discussed in Section 2, and intrinsic organization of the RVM and recruitment of PAG-RVM system are considered in Section 3. Additional sources of descending modulation include pontine noradrenergic cell groups (Pertovaara, 2006) and two areas of the caudal medulla discussed in Section 4, the dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM) (Tavares and Lima, 2007).
Section snippets
Descending control from the PAG distinguishes between the spinal processing of different sensory qualities, including different components of the pain signal
In the 40 years since Reynolds first described the phenomenon of stimulation-produced analgesia (Reynolds, 1969), the therapeutic potential of descending control has fuelled intense investigation of how descending systems interface with nociceptive circuitry of the dorsal horn. There is nevertheless much conflicting information, and many unknowns: to what extent and under what conditions are descending controls mediated by presynaptic versus postsynaptic mechanisms; what
Organization and recruitment of pain modulating circuitry of the RVM
The PAG does not project directly to the spinal cord. Instead, its principle descending projection is to the RVM, which can be considered the output of the midline pain-modulation system. The RVM is defined functionally, as the midline pontomedullary area in which electrical stimulation or opioid microinjection produces behavioral antinociception. It includes the nucleus raphe magnus and adjacent reticular formation, and projects diffusely to dorsal horn laminae important in nociceptive
Descending control from the caudal medulla
In addition to the PAG-RVM system, two areas of the caudal medulla, the dorsal reticular nucleus (DRt) and caudal lateral ventrolateral medulla (VLM), have also been implicated in descending control of dorsal horn nociceptive processing. The DRt is reciprocally connected with dorsal horn laminae important in nociception, and experimental stimulation of the DRt facilitates behavioral measures of nociception, implicating this region in a positive feedback loop that is closely tied to processing
Concluding remarks
Our understanding of pain mechanisms and pain control has in large part focused on the properties of primary afferent and dorsal horn nociceptive neurons and ascending pathways. The role of supraspinal processing has undergone a recent renaissance with the advent of functional imaging techniques, which have pointed to an interacting cortical “matrix”, rather than a “pain center” as underlying the pain experience. Nevertheless, a complete understanding of the neural basis of pain requires
Acknowledgments
BML was supported by the BBSRC and The Wellcome Trust. JLL was a BBSRC Case Student. MMH was supported by grants from NINDS (NS052364) and NIDA (DA05608). IT was supported by a grant from FCT (PTDC/SAU-OSM/64643/2006). We thank Andy Rekito for providing illustrations.
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