Hyperalgesia and allodynia are two forms of hypersensitivity that AC 55541 depend on peripheral as well as central alterations of sensory transmission following injury. A candidate for peripheral nociceptor sensitization is the cation-selective ion-channel TRPV1. The role of TRPV1 in hyperalgesia has been studied in various models where the contribution of TRPV1 to heat hyperalgesia during inflammatory states is well established. Mice lacking TRPV1 are characterized by attenuated development of heat hyperalgesia during tissue inflammation, similarly, genetic deletion of the Trpv1-Cre population leads to decreased heat hypersensitivity during inflammatory states. However, the specific transmission accounting for the development of different modalities of nerve injury-induced hypersensitivity involving TRPV1 neurons remains unknown. Initial reports have shown that TRPV1 is ubiquitous for the mediation of heat or punctuate hyperalgesia after nerve injury, suggesting that TRPV1 is only critical for hyperalgesia after certain types of tissue injury, excluding nerve damage. However, in models of neuropathic pain, expression levels of TRPV1 in undamaged neurons increase, whereas in damaged neurons they decrease. Also, peri-sciatic administration of capsaicin and QX-314 reduces both heat and mechanical hypersensitivity in the chronic constriction injury model, indicating that the TRPV1 receptor and population might be involved in the development of neuropathic pain. To define the role of the TRPV1 population in nerve injury, we here set out to further characterize the population and the neurotransmitters involved in the transmission via these primary afferents. A role for spinal glutamate in the development of chronic pain has been previously suggested. Pharmacological or antisense manipulation of glutamate receptors leads to reduced punctuate hyperalgesia following peripheral nerve injury and decreased reuptake of glutamate via spinal glutamate transporters can contribute to pathogenesis in different neuropathic pain models. It is currently unclear to which extent peripherally delivered glutamate contributes to these processes. Introduction of genetic tools, like conditional deletion of vesicular glutamate transporters, have provided an approach to silence glutamatergic signaling in defined primary afferent populations. The use of such mice has resulted in an increased knowledge of glutamate-mediated neurotransmission from peripheral neurons in different states of hypersensitivity.We have previously shown that VGLUT2- mediated transmission from all primary afferents is crucial for the development of heat, cold and punctuate hyperalgesia. By manipulating more specific neuronal A 412997 dihydrochloride populations, distinct roles of VGLUT2 and the population in question can be defined. Here, we have used a genetic approach to specifically delete Trpv1-Cre expressing neurons, or their expression of VGLUT2, to investigate the contribution from Trpv1-Cre neurons to the development of different modalities of nerve injury-associated hypersensitivity.