The molecular dynamics of pain control

Hunt, Stephen P.; Mantyh, Patrick W.

doi:10.1038/35053509

Cited by 525 publications

(369 citation statements)

References 95 publications

Supporting

Mentioning

345

Contrasting

Unclassified

Order By: Relevance

“…Even more striking is that a large percentage of these neurons do not fit into a traditional neurochemical pheno- type. For example, if one considers the classical markers of peptidergic and nonpeptidergic neurons (Hunt and Mantyh, 2001), one-third of TRPM8 TG neurons are immunoreactive for CGRP (even fewer in DRG), whereas none bind IB4. However, based on these criteria, over two-thirds of TRPM8 TG neurons fall outside of this classification (i.e., those that are CGRP and IB4 negative).…”

Section: Discussionmentioning

confidence: 99%

“…Peptidergic fibers, labeled by CGRP immunoreactivity, project to lamina I and the outer regions of lamina II (IIo) (McNeill et al, 1988;Zylka et al, 2005). In contrast, nonpeptidergic neurons labeled by IB4-binding project primarily to the inner region of lamina II (IIi), whereas lamina IIi and III can be visualized by labeling of interneurons expressing the ␥-isoform of protein kinase C (PKC␥) (Silverman and Kruger, 1988;Hunt and Mantyh, 2001;Zylka et al, 2005). In spinal cords of Trpm8 GFP mice, there was almost complete overlap of GFP-and CGRPlabeled fibers (Fig.…”

Section: Central Projections Of Trpm8 Fibers In the Dorsal Spinal Cordmentioning

confidence: 99%

“…Somatosensory neurons are routinely segregated into largely nonoverlapping subclasses based on a number of parameters, such as the extent of axonal myelination, or the presence of neuropeptides (Silverman and Kruger, 1988;Goldstein et al, 1991;Hunt and Mantyh, 2001). However, these markers do not select for the modality of stimuli that specific neurons detect, Figure 1.…”

Section: Trpm8 Is Expressed In Both Nociceptive and Non-nociceptive Smentioning

confidence: 99%

See 2 more Smart Citations

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Takashima¹,

Daniels²,

Knowlton³

et al. 2007

J. Neurosci.

192

214

View full text Add to dashboard Cite

Sensory nerves detect an extensive array of somatosensory stimuli, including environmental temperatures. Despite activating only a small cohort of sensory neurons, cold temperatures generate a variety of distinct sensations that range from pleasantly cool to painfully aching, prickling, and burning. Psychophysical and functional data show that cold responses are mediated by both C-and A␦-fibers with separate peripheral receptive zones, each of which likely provides one or more of these distinct cold sensations. With this diversity in the neural basis for cold, it is remarkable that the majority of cold responses in vivo are dependent on the cold and menthol receptor transient receptor potential melastatin 8 (TRPM8). TRPM8-null mice are deficient in temperature discrimination, detection of noxious cold temperatures, injury-evoked hypersensitivity to cold, and nocifensive responses to cooling compounds. To determine how TRPM8 plays such a critical yet diverse role in cold signaling, we generated mice expressing a genetically encoded axonal tracer in TRPM8 neurons. Based on tracer expression, we show that TRPM8 neurons bear the neurochemical hallmarks of both C-and A␦-fibers, and presumptive nociceptors and non-nociceptors. More strikingly, TRPM8 axons diffusely innervate the skin and oral cavity, terminating in peripheral zones that contain nerve endings mediating distinct perceptions of innocuous cool, noxious cold, and first-and second-cold pain. These results further demonstrate that the peripheral neural circuitry of cold sensing is cellularly and anatomically complex, yet suggests that cold fibers, caused by the diverse neuronal context of TRPM8 expression, use a single molecular sensor to convey a wide range of cold sensations.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Central Projections Of Trpm8 Fibers In the Dorsal Spinal Cordmentioning

confidence: 99%

Section: Trpm8 Is Expressed In Both Nociceptive and Non-nociceptive Smentioning

confidence: 99%

See 1 more Smart Citation

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Takashima¹,

Daniels²,

Knowlton³

et al. 2007

J. Neurosci.

192

214

View full text Add to dashboard Cite

show abstract

“…The sensory component of pain is defined as nociception and is required for survival and the maintenance of the integrity of the organism. However, sustained or chronic pain, particularly in humans, can result in secondary symptoms such as anxiety, depression, and a marked decrease in the quality of life (1,2). Specific cell types and several molecules have been identified that detect and regulate nociceptive activity.…”

mentioning

confidence: 99%

Cyclin-dependent kinase 5 activity regulates pain signaling

Pareek

Keller

Kesavapany

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

107

151

View full text Add to dashboard Cite

Several molecules and cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine͞threonine kinase implicated in the development and disease of the mammalian nervous system. The precise role of this kinase in sensory pathways has not been well characterized. Here we report a molecular role for Cdk5 in nociception. We identified the expression of Cdk5 and its activator p35 in nociceptive neurons, which is modulated during a peripheral inflammatory response. Increased calpain activity in sensory neurons after inflammation resulted in the cleavage of p35 to p25, which forms a more stable complex with Cdk5 and, consequently, leads to elevation of Cdk5 activity. p35 knockout mice (p35 ؊/؊ ), which exhibit significantly decreased Cdk5 activity, showed delayed responses to painful thermal stimulation compared with WT controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, were more sensitive to painful thermal stimuli than were controls. In conclusion, our data demonstrate a role for Cdk5͞p35 activity in primary afferent nociceptive signaling, suggesting that Cdk5͞p35 may be a target for the development of analgesic drugs.nociception ͉ inflammation ͉ dorsal root ganglia ͉ trigeminal ganglia ͉ spinal cord P ain is a combination of sensory (discriminative) and affective (emotional) components. The sensory component of pain is defined as nociception and is required for survival and the maintenance of the integrity of the organism. However, sustained or chronic pain, particularly in humans, can result in secondary symptoms such as anxiety, depression, and a marked decrease in the quality of life (1, 2). Specific cell types and several molecules have been identified that detect and regulate nociceptive activity. Additionally, the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain have been elucidated, but the underlying molecular mechanisms remain unclear. So far, studies using genetically modified mice, antisense knockdowns in cells, gene expression assays (including DNA microarray-based expression profiling), and linkage mapping have identified several genes the expression levels of which are directly or indirectly affected during pain sensation and͞or that are involved in modulating pain (3). As a result, the number of proteins encoded by these genes continues to expand, and further investigation of their participation in pain pathways is required.Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (which belong to a family of small proline-directed serine͞threonine kinases), is mainly active in postmitotic neurons because of the selective neuronal expression of its activators, p35 and p39 (4, 5). Transcriptional and translational regulation of p35 and p39 plays a key role in the maintenance of normal Cdk5 activity. We and others have previously reported critical role...

show abstract

“…This tachykinin has been suggested to be involved in numerous functions, including transmission of noxious stimuli to the spinal cord (Hunt and Mantyh, 2001). The SP is released by dorsal root ganglion (DRG) afferents and can act on neurons of the dorsal horns, a laminar structure that receives somatosensory inputs.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Localization of Substance P And Cholecystokinin in the Dorsal Root Ganglia and Spinal Cord of the Bottlenose Dolphin (Tursiops truncatus)

Bombardi

Grandis

Nenzi

et al. 2010

The Anatomical Record

View full text Add to dashboard Cite

The presence of substance P (SP) and cholecystokinin (CCK) immunoreactive neurons was examined in the bottlenose dolphin dorsal root ganglia (DRGs) and spinal cord by immunohistochemical techniques. SPpositive and CCK-immunoreactive neurons were respectively $50% and 1% of the total number of ganglion cells examined and especially belonged to small and medium-sized cell populations. Using double labeling techniques we observed that SP-and CCK-immunoreactivity coexisted in a very low number of primary afferent neurons (2.7%). Few SPimmunoreactive (IR) neurons (2.7%) were also CCK-positive. On the contrary, 65% of CCK-immunoreactive neurons contained SP. Interestingly, we observed CCK-immunoreactive satellite glial cells located around large cell class somata. Virtually no SP-IR and CCK-positive neurons were surrounded by peripheral CCK-immunoreactive satellite glial cells. The SP-IR and CCK-positive nerve fibers were particularly conspicuous in the superficial layers of the spinal cord. The present study indicates that SP and CCK only partially overlap in the thoracic, lumbar, and caudal DRGs of the bottlenose dolphin, suggesting that the majority of SP-IR ganglion neurons are lacking in CCK-immunoreactivity. The role of SPcontaining DRG neurons is discussed also in relation to the huge vascular spinal retia mirabilia typical of cetaceans. Anat Rec, 293:477-484, 2010. V V C 2010 Wiley-Liss, Inc.

show abstract

The molecular dynamics of pain control

Cited by 525 publications

References 95 publications

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Cyclin-dependent kinase 5 activity regulates pain signaling

Immunohistochemical Localization of Substance P And Cholecystokinin in the Dorsal Root Ganglia and Spinal Cord of the Bottlenose Dolphin (Tursiops truncatus)

Contact Info

Product

Resources

About