Despite the impact of chronic pain on the quality of life in patients, including changes to affective state and daily life activities, rodent preclinical models rarely address this aspect of chronic pain. To better understand the behavioral consequences of the tissue and nerve injuries typically used to model neuropathic and inflammatory pain in mice, we measured home cage and affective state behaviors in animals with spared nerve injury (SNI), chronic constriction injury (CCI) or intraplantar CFA. Mechanical hypersensitivity is prominent in each of these conditions and persists for many weeks. Home cage behavior was continuously monitored for 16 days in a system that measures locomotion, feeding and drinking and allows for precise analysis of circadian patterns. When monitored after injury, animals with SNI and CFA behaved no differently from controls in any aspect of daily life. Animals with CCI were initially less active, but the difference between CCI and controls disappeared by 2 weeks after injury. Further, in all pain models, there was no change in any measure of affective state. We conclude that in these standard models of persistent pain, despite the development of prolonged hypersensitivity, the mice do not have significantly altered "quality of life". As alteration in daily life activities is the feature that is so disrupted in patients with chronic pain, our results suggest that the models used here do not fully reflect the human conditions and point to a need for development of a murine chronic pain model in which lifestyle changes are manifest.

SUMMARY To what extent dorsal horn interneurons contribute to the modality specific processing of pain and itch messages is not known. Here we report that loxp/cre-mediated CNS deletion of TR4, a testicular orphan nuclear receptor, results in loss of many excitatory interneurons in the superficial dorsal horn, but preservation of primary afferents and spinal projection neurons. The interneuron loss is associated with a near complete absence of supraspinally-integrated pain and itch behaviors, elevated mechanical withdrawal thresholds and loss of nerve injury-induced mechanical hypersensitivity, but reflex responsiveness to noxious heat, nerve injury-induced heat hypersensitivity and tissue injury-induced heat and mechanical hypersensitivity are intact. We conclude that different subsets of dorsal horn excitatory interneurons contribute to tissue and nerve injury-induced heat and mechanical pain and that the full expression of supraspinally-mediated pain and itch behaviors cannot be generated solely by nociceptor and pruritoceptor activation of projection neurons; concurrent activation of excitatory interneurons is essential.

Dorsal root ganglia (DRG) neurons, including the nociceptors that detect painful thermal, mechanical, and chemical stimuli, transmit information to spinal cord neurons via glutamatergic and peptidergic neurotransmitters. However, the specific contribution of glutamate to pain generated by distinct sensory modalities or injuries is not known. Here we generated mice in which the vesicular glutamate transporter 2 (VGLUT2) is ablated selectively from DRG neurons. We report that conditional knockout (cKO) of the Slc17a6 gene encoding VGLUT2 from the great majority of nociceptors profoundly decreased VGLUT2 mRNA and protein in these neurons, and reduced firing of lamina I spinal cord neurons in response to noxious heat and mechanical stimulation. In behavioral assays, cKO mice showed decreased responsiveness to acute noxious heat, mechanical, and chemical (capsaicin) stimuli, but responded normally to cold stimulation and in the formalin test. Strikingly, although tissue injury-induced heat hyperalgesia was lost in the cKO mice, mechanical hypersensitivity developed normally. In a model of nerve injuryinduced neuropathic pain, the magnitude of heat hypersensitivity was diminished in cKO mice, but both the mechanical allodynia and the microgliosis generated by nerve injury were intact. These findings suggest that VGLUT2 expression in nociceptors is essential for normal perception of acute pain and heat hyperalgesia, and that heat and mechanical hypersensitivity induced by peripheral injury rely on distinct (VGLUT2 dependent and VGLUT2 independent, respectively) primary afferent mechanisms and pathways.nociceptor | inflammatory pain | electrophysiology | neuroanatomy P rimary afferent neurons of the dorsal root ganglia (DRG) detect a wide range of stimulus modalities and intensities (1). This is particularly true for nociceptors, which are the neurons specialized to detect noxious stimuli. Not only do subsets of nociceptors express different repertoires of neuropeptides, receptors, and ion channels, but they also project to different laminae in the spinal cord where they engage different CNS circuits (2-4). Importantly, studies in rodents in which different nociceptor populations have been deleted revealed remarkably selective behavioral deficits (e.g., heat, mechanical, or chemical pain), demonstrating the existence of behaviorally relevant peripheral-labeled lines for different modalities of pain (5-8).Whether the modality-specific contribution of sensory neurons to acute pain and to injury-induced hypersensitivity states is also manifest at the level of the different neurotransmitters expressed by these neurons is still not known. Interestingly, previous pharmacological and genetic studies that disrupted neuropeptide function did not find a modality-specific loss of pain processing (9). Here we turned our attention to glutamate, which is presumed to be released by all DRG neurons to activate second-order spinal cord neurons.Because pharmacological blockade of glutamate signaling would nonselectively inhibit the centr...

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