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

Abstract

Ablating or functionally compromising sets of sensory neurons has provided important insights into peripheral modality-specific wiring in the somatosensory system. Inflammatory hyperalgesia, cold pain, and noxious mechanosensation have all been shown to depend upon Na v 1.8-positive sensory neurons. The release of fastacting neurotransmitters, such as glutamate, and more slowly released neuropeptides, such as substance P (SP), contribute to the diversified responses to external stimuli. Here we show that deleting Vglut2 in Na v 1.8 Cre -positive neurons compromised mechanical pain and NGF-induced thermal hyperalgesia, whereas tactile-evoked sensation, thermal, formalin-evoked, and chronic neuropathic pain were normal. However, when Vglut2 f/f ;Na v 1.8 Cre mice were injected with a SP antagonist before the formalin test, the second phase pain response was nearly completely abolished, whereas in control mice, the pain response was unaffected. Our results suggest that VGLUT2-dependent signaling originating from Na v 1.8-positive neurons is a principal sensing mechanism for mechanical pain and, together with SP, inflammatory pain. These data define sets of primary afferents associated with specific modalities and provide useful genetic tools with which to analyze the pathways that are activated by functionally distinct neuronal populations and transmitters.dorsal root ganglia | mouse genetics | neuronal network | co-transmission | sensory signaling

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

“…VGLUT2, which is the predominant transporter in the nociceptive primary afferent population (Brumovsky et al, 2007;Lagerström et al, 2010Lagerström et al, , 2011Scherrer et al, 2010;Rogoz et al, 2012), overlaps to a large extent with the TRPV1 population ( Fig. 1) Lagerström et al, 2010).…”

“…The evidence supporting this theory include increased levels of glutamate in peripheral tissues in response to inflammation (Omote et al, 1998;deGroot et al, 2000) and reduced hyperalgesia after peripheral inflammation in response to various metabotropic glutamate receptors antagonists (Walker et al, 2001;Lee et al, 2007). The TRPV1 population of primary afferent neurons and trigeminal neurons have been shown to overlap with markers for glutamatergic transmission Lagerström et al, 2010Lagerström et al, , 2011, and TRPV1 antagonists are known to inhibit glutamatergic transmission after peripheral inflammation (Lappin et al, 2006). It is however not known how glutamate contributes to TRPV1-associated hyperalgesia after peripheral inflammation, presumably because studies of glutamate in specific neuronal populations have been lacking efficient tools.…”

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

“…It is well known that specific sets of sensory neurons are involved in different pain modalities and, more importantly, different types of chronic pain (46)(47)(48)(49). The IB4 + subset of DRG neurons specifically responds to inflammatory stimuli injected intraplantarly (46)(47)(48)(49).…”

Nogo Receptor Homolog NgR2 Expressed in Sensory DRG Neurons Controls Epidermal Innervation by Interaction with Versican

“…Primer sequences for GFRa1, GFRa2, NGF, BDNF, GDNF, and NT3 were taken from Jankowski et al (2009), and for both isoforms of c-Ret from Kojima et al (2011). Primer sequences for Asic1a and Asic2a were taken from Sherwood et al (2011), and for Asic3a from Hattori et al (2009).…”

“…NgR1 and NgR2 were identified as axonal glycosylphosphatidylinositol-anchored proteins with specific binding properties for myelin-associated growth inhibitors in the CNS (Fournier et al, 2001;Venkatesh et al, 2005). In addition, NgR1 and NgR3, but not NgR2, were shown to associate with selective glycosaminoglycan (GAG) side chains of CSPGs (Dickendesher et al, 2012).…”