Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors

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Abstract
The skin can become hypersensitive following injury, inflammation or sunburn, when even the lightest touch can cause intense pain. This usually disappears quickly, but in some cases it persists, causing debilitating pain that is hard to treat, in part because the identity of the neural circuits involved is not known. Now a novel class of primary sensory neurons has been implicated in these chronic pain syndromes. Mutant mice lacking the unconventional vesicular glutamate transporter VGLUT3 become less sensitive to intense mechanical pain and are no longer hypersensitive to light touch after injury. The VGLUT3+ neurons in the dorsal root ganglion are unmyelinated low-threshold mechanoreceptors that have been implicated in pleasant touch sensations in humans, and it appears that during post-injury hypersensitivity they instead convey a sensation of pain. This suggests new avenues for experiment and therapeutic intervention. Despite the contribution of mechanical pain to the morbidity associated with inflammation and trauma, the primary sensory neurons that convey this sensation have not been identified. Using knockout mice, the loss of the low abundance vesicular glutamate transporter VGLUT3, expressed by a small subset of peripheral sensory neurons projecting to areas implicated in persistent pain caused by injury, is now shown to specifically impair mechanical pain sensation. 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 (also known as SLC17A8). 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. Because the different VGLUT isoforms generally have a non-redundant pattern of expression3, we used Vglut3 knockout mice to assess the role of VGLUT3+ primary afferents in the behavioural 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-/- mice now indicates a critical role for C-LTMRs in the mechanical hypersensitivity caused by injury.