Mechanical Allodynia Circuitry in the Dorsal Horn Is Defined by the Nature of the Injury

• Published in: Neuron (Cambridge, Mass.) Vol. 109; no. 1; pp. 73 - 90.e7
• Main Authors: Peirs, Cedric, Williams, Sean-Paul G., Zhao, Xinyi, Arokiaraj, Cynthia M., Ferreira, David W., Noh, Myung-chul, Smith, Kelly M., Halder, Priyabrata, Corrigan, Kelly A., Gedeon, Jeremy Y., Lee, Suh Jin, Gatto, Graziana, Chi, David, Ross, Sarah E., Goulding, Martyn, Seal, Rebecca P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.01.2021; Elsevier Limited; Elsevier
• Subjects: Ablation; Amino Acid Transport Systems, Acidic - metabolism; Animals; Calretinin; Cholecystokinin; Cognitive science; Dorsal horn; Etiology; Female; Glutamic acid transporter; Hyperalgesia - metabolism; Hyperalgesia - pathology; Inflammation; inflammatory pain; Injuries; Kinases; Ligands; Male; mechanical allodynia; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Net - chemistry; Nerve Net - metabolism; Nerve Net - pathology; neural circuitry; Neural networks; Neurons; neuropathic pain; Neuroscience; Pain; Pain Measurement - methods; Pain perception; Population; Protein kinase C; protein kinase C gamma; Rodents; Spinal cord; Spinal Cord Dorsal Horn - chemistry; Spinal Cord Dorsal Horn - metabolism; Spinal Cord Dorsal Horn - pathology; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - pathology; vesicular glutamate transporter 3; protein kinase C gamma; pain; neuropathic pain; vesicular glutamate transporter 3; dorsal horn; neural circuitry; cholecystokinin; inflammatory pain; mechanical allodynia; calretinin
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2020.10.027

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. [Display omitted] •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.