Reduced activity in capsaicin-responsive spinal

neurons was paralleled by a 5-fold increase in tonic and evoked activity in icilin/cold-responsive spinal neurons. These data suggest that CGRPα afferents Epigenetics Compound Library in vivo (50% of which are TRPV1+) tonically cross-inhibit icilin/cold-responsive spinal neurons, with cross-inhibition mediated through capsaicin-responsive interneurons. Indeed, a subset of capsaicin-responsive spinal neurons monosynaptically inhibit icilin-responsive spinal neurons (Zheng et al., 2010), highlighting a direct line of communication between these modality-selective circuits at the spinal level. Ablation of CGRPα/heat neurons removes this tonic inhibition, causing central disinhibition and hypersensitivity/allodynia to cold stimuli. Our findings do not support the pattern theory of somatosensation, which

is based on the idea that different frequencies and firing patterns in sensory neurons encode different sensory experiences, such as heat and cold (Ma, 2010). Instead, our findings suggest that tonic activity in a modality-selective class of neurons—TRPM8 neurons—is directly responsible for driving enhanced cold sensitivity when a different class of neurons—CGRPα DRG neurons—is ablated. It should be possible to test this prediction in future studies with TRPM8 antagonists or Trpm8−/− mice, especially given that tonic activity in the majority of cold-sensitive Stem Cell Compound Library solubility dmso Rolziracetam C-fibers is reduced when Trpm8 is deleted ( Bautista et al., 2007). For

example, deletion of Trpm8 may rescue some of the enhanced cold and thermoregulatory phenotypes in CGRPα DRG neuron-ablated mice. Our findings also do not entirely support the labeled line theory of somatosensation (Ma, 2010), as this would imply that CGRPα/heat and TRPM8/cold pathways remain segregated and do not interact (anatomically or functionally) in the periphery, spinal cord, or the brain. If these modality-selective circuits remain segregated from one another, this raises the question of how else could CGRPα DRG neuron ablation simultaneously enhance activity in cold-responsive spinal neurons and reduce activity in capsaicin/heat-responsive neurons. This might occur, for example, if our genetic ablation was leaky and eliminated additional classes of neurons that synapse directly or indirectly with these heat- and cold-responsive spinal neurons. However, we found no evidence that any classes of spinal neurons were missing in DTX-treated animals, including CGRPα-GFP spinal neurons (Figures 2M–2R, Table S1). In fact, given that the floxed GFP reporter (Figure 1A) was expressed (and hence not excised) in these spinal neurons (Figures 2O and 2R), this further confirms the specificity of Advillin-Cre for sensory ganglia over spinal cord.