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Abstract: Chronic pain remains a significant problem due to its prevalence, impact, and limited therapeutic options. Progress in addressing chronic pain is dependent on a better understanding of underlying mechanisms. Although the available evidence suggests that changes within the central nervous system contribute to the initiation and maintenance of chronic pain, it also suggests that the primary afferent plays a critical role in all phases of the manifestation of chronic pain in most of those who suffer. Most notable among the changes in primary afferents is an increase in excitability or sensitization. A number of mechanisms have been identified that contribute to primary afferent sensitization with evidence for both increases in pronociceptive signaling molecules, such as voltage-gated sodium channels, and decreases in antinociceptive signaling molecules, such as voltage-dependent or calcium-dependent potassium channels. Furthermore, these changes in signaling molecules seem to reflect changes in gene expression as well as posttranslational processing. A mechanism of sensitization that has received far less attention, however, is the local or axonal translation of these signaling molecules. A growing body of evidence indicates that this process not only is dynamically regulated but also contributes to the initiation and maintenance of chronic pain. Here, we review the biology of local translation in primary afferents and its relevance to pain pathobiology. [ABSTRACT FROM AUTHOR]

Summary Persistent mechanical hypersensitivity that occurs in the setting of injury or disease remains a major clinical problem largely because the underlying neural circuitry is still not known. Here we report the functional identification of key components of the elusive dorsal horn circuit for mechanical allodynia. We show that the transient expression of VGLUT3 by a discrete population of neurons in the deep dorsal horn is required for mechanical pain and that activation of the cells in the adult conveys mechanical hypersensitivity. The cells, which receive direct low threshold input, point to a novel location for circuit initiation. Subsequent analysis of c-Fos reveals the circuit extends dorsally to nociceptive lamina I projection neurons, and includes lamina II calretinin neurons, which we show also convey mechanical allodynia. Lastly, using inflammatory and neuropathic pain models, we show that multiple microcircuits in the dorsal horn encode this form of pain. [ABSTRACT FROM AUTHOR]

The spinal dorsal horn is a major site for the induction and maintenance of mechanical allodynia, but the circuitry that underlies this clinically important form of pain remains unclear. The studies presented here provide strong evidence that the neural circuits conveying mechanical allodynia in the dorsal horn differ by the nature of the injury. Calretinin (CR) neurons in lamina II inner convey mechanical allodynia induced by inflammatory injuries, while protein kinase C gamma (PKCγ) neurons at the lamina II/III border convey mechanical allodynia induced by neuropathic injuries. Cholecystokinin (CCK) neurons located deeper within the dorsal horn (laminae III–IV) are important for both types of injuries. Interestingly, the Maf + subset of CCK neurons is composed of transient vesicular glutamate transporter 3 (tVGLUT3) neurons, which convey primarily dynamic allodynia. Identification of an etiology-based circuitry for mechanical allodynia in the dorsal horn has important implications for the mechanistic and clinical understanding of this condition. • CR neurons are important for mechanical allodynia in inflammatory injuries • PKCγ neurons are important for mechanical allodynia in neuropathic injuries • CCK and tVGLUT3 neurons in deeper laminae convey both types of injuries • The Maf + subset of CCK neurons encompasses tVGLUT3 and conveys dynamic allodynia Peirs et al. identified distinct spinal cord microcircuits that underlie mechanical allodynia, depending on the injury type. The neurons engaged after neuropathic or inflammatory injuries include populations that express CCK, tVGLUT3, CR, and PKCγ. [ABSTRACT FROM AUTHOR]