The paradox of pain from tooth pulp: Low-threshold “algoneurons”?

Fried, Kaj; Sessle, Barry J.; Devor, Marshall

doi:10.1016/j.pain.2011.08.004

Cited by 78 publications

(86 citation statements)

References 45 publications

(71 reference statements)

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“…The Mrgprd-negative non-peptidergic afferents may constitute the bulk of the medium-to large-diameter pulpal afferents. Some of these may be myelinated afferents that were proposed to transmit mechanical pain within pulp (Fried et al, 2011), which needs to be proven. What could be the role of the Mrgprdpositive pulpal afferents?…”

Section: Discussionmentioning

confidence: 99%

“…Increased intra-pulpal interstitial pressure under inflammation due to the limited compliance of pulpal tissues also evokes or aggravates tooth pain (Hakumaki and Närhi, 1973;Heyeraas and Berggreen, 1999). A cellular and molecular matrix of such mechanisms has been hypothesized (Hermanstyne et al, 2008;Magloire et al, 2010;Fried et al, 2011;Kim et al, 2011) but is still poorly understood.…”

Section: Introduction Pmentioning

confidence: 99%

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Projection of Non-peptidergic Afferents to Mouse Tooth Pulp

2012

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A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. AbstrAct A large proportion of pulpal nociceptors are known to contain neuropeptides such as CGRP. However, the projection of non-peptidergic nociceptors to tooth pulp is controversial. Recently, the nonpeptidergic subset of nociceptors has been implicated in mechanical pain in the skin. Since mechanical irritation of pulpal nociceptors is critical for evoking tooth pain under pathophysiological conditions, we investigated whether the non-peptidergic afferents project to tooth pulp as potential mechanotransducing afferents. For clear visualization of the non-peptidergic afferents, we took advantage of a recently generated knock-in mouse model in which an axonal tracer, farnesylated green fluorescence protein (GFP), is expressed from the locus of a sensory neuron-specific gene, Mrgprd. In the trigeminal ganglia (TG), we demonstrated that GFP is exclusively expressed in afferents binding to isolectin B4 (IB4), a neurochemical marker of non-peptidergic nociceptors, but is rarely co-localized with CGRP. Retrograde labeling of pulpal afferents demonstrated that a low proportion of pulpal afferents was co-localized with GFP. Immunohistochemical detection of the axonal tracer revealed that GFP-positive afferent terminals were densely projected into the tooth pulp. These results provide convincing evidence that non-peptidergic nociceptors are projected into the tooth pulp and suggest a potential role for these afferents in tooth pain.

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Section: Discussionmentioning

confidence: 99%

Section: Introduction Pmentioning

confidence: 99%

Projection of Non-peptidergic Afferents to Mouse Tooth Pulp

2012

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“…This does not contradict a role in nociception, because most nerve fibers innervating teeth get myelinated, even reaching large A-fiber conduction velocity, when they leave the tooth pulp. Nonetheless, pain is the only sensation that these trigeminal "algoneurons" mediate (211). NOS-containing axons were also revealed in dental pulp and gingiva of cats and dogs (439).…”

Section: A Biosynthesis and General Features Of Nitric Oxidementioning

confidence: 95%

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

Pethő

Reeh

2012

Physiological Reviews

240

200

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Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs.

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“…In addition, electromicroscopic studies and measurement of conduction velocities suggest that most of the parental axon of pulpal neurons are medium to large myelinated neurons [14,15]. More recent literature has proposed that majority of dental afferent neurons are non-nociceptive low-threshold mechanoreceptors [16].…”

Section: Neuroanatomy Of a Toothmentioning

confidence: 99%

“…It is interesting that all of the mechanosensitive nerve fibers were myelinated A fibers according to conduction velocities [60]. In addition, it was proposed that majority of dental afferent neurons are non-nociceptive low-threshold mechanoreceptors [16], based on observation that most of dental afferents are medium to large myelinated Aβ fibers [14,15,61,62]. It is possible that TRPV2 is the key transducer molecule since TRPV2 was preferentially detected in medium to large neurons [24,25], and stretchinduced activation of TRPV2 was reported in vascular smooth muscle [63].…”

Section: Mechanosensitive Trp Channels In Neuronsmentioning

confidence: 99%

TRP Channels in Dental Pain

Chung

Oh²

2013

TOPAINJ

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Despite the high incidence of dental pain, the mechanism underlying its generation is mostly unknown. Functional expression of temperature-sensitive transient receptor potential (thermo-TRP) channels, such as TRPV1, TRPV2, TRPM8, and TRPA1 in dental primary afferent neurons and TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3 in odontoblasts, has been demonstrated and suggested as responsible for dental pain elicited by hot and cold food. However, dental pain induced by light touch or sweet substance cannot be explained by the role of thermo-TRP channels. Most of current therapeutics of dentin hypersensitivity is based on hydrodynamic theory, which argues that light stimuli such as air puff and temperature changes cause fluid movement within dentinal tubule, which is then transduced as pain. To test this theory, various TRP channels as candidates of cellular mechanotransducers were studied for expression in dental primary afferents and odontoblasts. The expression of TRPV1, TRPV2, TRPA1, TRPV4, and TRPM3 in trigeminal neurons and TRPV1, TRPV2, TRPV3, TRPV4 and TRPM3 in odontoblasts has been revealed. However, their roles as cellular mechanotransducers are controversial and contribution to generation of dental pain is still elusive. This review discusses recent advances in understanding of molecular mechanism underlying development of dental pain.

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The paradox of pain from tooth pulp: Low-threshold “algoneurons”?

Cited by 78 publications

References 45 publications

Projection of Non-peptidergic Afferents to Mouse Tooth Pulp

Projection of Non-peptidergic Afferents to Mouse Tooth Pulp

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

TRP Channels in Dental Pain

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