Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors

Abstract

Mechanical pain contributes to the morbidity associated with inflammation and trauma, but primary sensory neurons that convey the sensation of acute and persistent mechanical pain have not been identified. Dorsal root ganglion (DRG) neurons transmit sensory information to the spinal cord using the excitatory transmitter glutamate1, a process that depends on glutamate transport into synaptic vesicles for regulated exocytotic release. Here we report that a small subset of cells in the DRG expresses the low abundance vesicular glutamate transporter VGLUT3. In the dorsal horn of the spinal cord, these afferents project to lamina I and the innermost layer of lamina II, which has previously been implicated in persistent pain caused by injury2. Since the different VGLUT isoforms generally exhibit a nonredundant pattern of expression3, we used VGLUT3 knock-out (KO) mice to assess the role of VGLUT3+ primary afferents in the behavioral response to somatosensory input. The loss of VGLUT3 specifically impairs mechanical pain sensation and in particular the mechanical hypersensitivity to normally innocuous stimuli that accompanies inflammation, nerve injury and trauma. Direct recording from VGLUT3+ neurons in the DRG further identifies them as a poorly understood population of unmyelinated, low threshold mechanoreceptors (C-LTMRs)4,5. The analysis of VGLUT3 KO mice now indicates a critical role for C-LTMRs in the mechanical hypersensitivity caused by injury.

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

“…However, as the anatomy of the peptidergic and nonpeptidergic nociceptors appears normal in cKO mice, this seems unlikely. As to the residual pain responsiveness, several systems could contribute, including VGLUT2+ and Cre-negative afferents, VGLUT2-negative afferents implicated in nociceptive processing (notably the NF200+ VGLUT3-expressing afferents) (33), and perhaps peptidergic function in nociceptors from which VGLUT2 was deleted.…”

“…In this regard, large-diameter myelinated Aβ fibers, or low-threshold C fibers, which preferentially express VGLUT1 and VGLUT3, respectively, appear better positioned to contribute. Both of these afferent populations target the inner part of lamina II and the dorsal part of lamina III, a region critical for the development of mechanical allodynia/hypersensitivity after injury (33,(35)(36)(37). In fact, mice with a deletion of VGLUT3 show reduced mechanical allodynia (33), with no effect on heat hyperalgesia, suggesting complementary roles of the VGLUT2-and VGLUT3-expressing afferent populations following injury.…”

“…Both of these afferent populations target the inner part of lamina II and the dorsal part of lamina III, a region critical for the development of mechanical allodynia/hypersensitivity after injury (33,(35)(36)(37). In fact, mice with a deletion of VGLUT3 show reduced mechanical allodynia (33), with no effect on heat hyperalgesia, suggesting complementary roles of the VGLUT2-and VGLUT3-expressing afferent populations following injury. Our findings clearly emphasize the functional diversity of primary afferent neurons and provide further support for the existence of behaviorally relevant peripheral labeled lines for the perception of distinct pain modalities.…”

The Role of Sensory Fiber Demography in Trigeminal and Postherpetic Neuralgias

“…Ultimately, most patients with PHN describe multiple types of pain, such as constant, deep, burning, paroxysmal, and lancinating. However, it is important to mention the possible contributions of C-low-threshold mechanoreceptors for tactile allodynia, reported in a recent publication (Seal et al, 2009). In addition, other sensory disturbances frequently associated with PHN are paresthesia, dysesthesia, hyperalgesia, and itching (Dworkin et al, 2008;Truini et al, 2008).…”

A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain

“…They are expressed in mostly nonoverlapping patterns in the nervous system and in DRGs, where the expression of VGLUT1 dominates in nonnociceptive neurons, VGLUT2 in nociceptors (9), and VGLUT3 in a small subset of DRG C-low threshold mechanoreceptors (13). Mice with one disrupted Vglut2 allele display intact acute pain responses, but show a reduced response to cold and mechanical stimuli after spared nerve injury (14).…”