Dorsal Horn Circuits for Persistent Mechanical Pain

Abstract

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.

Making sense out of spinal cord somatosensory development

“…Indeed, extensive molecular analysis of the V1 population in the ventral spinal cord has identified up to 50 transcriptionally defined subsets that distinguish neuronal populations with unique physiological properties and connectivity Gabitto et al, 2016). Similarly, identification of molecularly and developmentally defined populations in the dorsal horn is beginning to distinguish microcircuits that mediate particular somatosensory behaviors, such as mechanical allodynia and proprioception (Duan et al, 2014;Peirs et al, 2015;Yuengert et al, 2015). Altogether, identifying these circuits will establish the foundation for developing new therapies to treat neuropathic conditions and spinal cord injury.…”

“…Further dissection of dI5/dIL B lineages has shown that the RORα + subset is in part responsible for dynamic light touch, as discussed above (Bourane et al, 2015b), while noxious thermosensation appears to derive from a LMX1B + population -potentially the neurons in lamina I that contribute to the spinothalamic tract (STT) division of the ALS (Szabo et al, 2015;Todd, 2010). Meanwhile, at least three subpopulations (positive for somatostatin, SOM, in laminae II-III, calretinin in the inner part of lamina II and the transient vesicular glutamate transporter 3, VGLUT3, in laminae II-III) are important for mechanical allodynia, a condition in which touch becomes painful after injury (Duan et al, 2014;Peirs et al, 2015). Assignment of the SOM + and transient VGLUT3 populations to the dI5/dIL B lineage is based on their excitatory nature and their expression of Lbx1 during development.…”

“…Assignment of the SOM + and transient VGLUT3 populations to the dI5/dIL B lineage is based on their excitatory nature and their expression of Lbx1 during development. The origin of the excitatory calretinin population is mixed because most, but not all cells are derived from the Lbx1 lineage (Duan et al, 2014;Peirs et al, 2015). The SOM + population makes up a large proportion (∼59%) of the excitatory interneurons in lamina II (Gutierrez-Mecinas et al, 2016).…”

“…6), thus allowing Aβ activation of SOM + neurons to turn touch into pain (Duan et al, 2014). Transient VGLUT3 cells, which reside predominantly in lamina III, an area of the dorsal horn associated with touch, have been suggested to reside at an entry point to the mechanical allodynia pathway (Peirs et al, 2015).…”

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…In painful neuropathy, ionotropic and metabotropic glutamate receptors exhibit phosphorylation and changes in trafficking that increase excitatory postsynaptic potential (EPSP) frequency and amplitude [62][63][64]. Increased post-synaptic activity is also achieved by alterations in glutamate homeostasis, resulting from increased expression of the vesicular glutamate transporters Vglut2 and Vglut3 in the superficial and deep dorsal horn, respectively [65]. This glutamate accumulation in synaptic vesicles is thought to increase EPSP amplitudes [66].…”