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To the descending pain-control system in rats, inflammation-induced primary and secondary hyperalgesia are two different things

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Abstract

The periaqueductal gray matter and the rostral ventromedial medulla (RVM), with its projections to the spinal dorsal horn, constitute the efferent channel of the ‘descending pain-control system’. Noxious stimulation of a peripheral tissue causes more pain if this tissue is inflamed (primary hyperalgesia). In such cases, stimulation of neighboring but uninflamed tissues also becomes more painful (secondary hyperalgesia). In animal models of inflammation, the descending pain-control system sends down, simultaneously, inhibitory and facilitatory influences, but inhibition predominates for primary hyperalgesia while facilitation predominates for secondary hyperalgesia. Descending inhibition and facilitation during peripheral inflammation are due not only to previously existing descending modulation, but also to inflammation-induced changes in RVM which involve receptors for NMDA, AMPA, cholecystokinin and neurotensin, as well as synthesis of enkephalins and nitric oxide.

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      Interestingly, Urban and Gebhart (1999) reported that blocking the RVM reversed secondary hyperalgesia (i.e., hyperalgesia adjacent to the injured region) to heat in monoarthritic or mustard oil-treated animals but failed to reduce primary hyperalgesia (i.e., hyperalgesia in the injured region) in animals with paw inflammation. This result is in line with the hypothesis that the RVM-mediated descending modulation of spinal nociception may vary from inhibition to facilitation depending on whether the spinal neuron receives inputs from the inflamed/injured area or from adjacent areas, respectively (Vanegas, 2004; Vanegas and Schaible, 2004). The dorsomedial nucleus of the hypothalamus (DMH) is among the supramedullary structures that have been shown to contribute to descending pain control through a relay in the RVM (Heinricher et al., 2009).

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      It is not known if CCK receptors they are located on neurons that possess NK-1Rs or on separate neurons. The same is true for other neurotransmitter systems that contribute to descending facilitation from the RVM, including neurotensin (Fields et al., 1991; Smith et al., 1997; Urban and Gebhart, 1997; Vanegas, 2004), brain-derived neurotrophic factor (Guo et al., 2006), and tumor necrosis factor-alpha (Wei et al., 2008). Further studies of anatomical and neurochemical mechanisms of multiple descending facilitatory pathways and their interactions are needed.

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      Descending pathways were initially shown to decrease pain transmission and produce antinociception (Criswell, 1976; Basbaum and Fields, 1978, 1984; Dostrovsky et al., 1983; Aimone and Gebhart, 1986; Behbehani, 1995). However, it is now accepted that descending systems can also facilitate nociceptive transmission and contribute to hyperalgesia (see reviews by Porreca et al. (2002), Vanegas (2004) and Suzuki et al. (2004a)). The RVM, which includes the Nucleus Raphe Magnus, the Nucleus Reticularis Gigantocellularis, the Nucleus Gigantocellularis pars alpha, and the Nucleus Paragigantocellularis lateralis, plays an important role in spinal nociceptive processing as a relay structure of descending modulation (Basbaum and Fields, 1984; Fields et al., 1991; Watkins et al., 1998; Urban and Gebhart, 1999; Urban et al., 1999a,b; Millan, 2002), including facilitation of nociceptive transmission and the development of hyperalgesia.

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