Pictured
Peripheral and spinal circuits involved in mechanical allodynia Alice Arcourt, Stefan G. Lechner *
S
ensory information from nociceptors and touch receptors, such as Aβ-fiber mechanoreceptors and C-fiber low-threshold mechanoreceptors (C-LTMRs), is normally relayed and processed by separate neural circuits in the spinal cord.19 After nerve injury or inflammation, however, touch-related information is also relayed to nociceptive circuits in the superficial dorsal horn, which results in touch-evoked pain.16 Here, we depict the spinal circuits that facilitate this modality crosstalk and form the cellular basis of mechanical allodynia. A role of Aβ fibers in allodynia was originally proposed by human studies showing that compression block of Aβ fibers abolishes touch-evoked pain.3,7 Subsequent studies confirmed that after nerve injury, neurokinin-1 receptor (NK1R) expressing projection neurons in lamina I receive excitatory input from Aβ fibers via a preexisting polysynaptic connection that includes somatostatin (SOM) expressing interneurons, which also receive input from nociceptors.2,6,17 This connection is normally inhibited by dynorphin-/ GAD67-expressing GABAergic interneurons in lamina II,4,6 the activity of which is controlled by polysynaptic input from Aβ fibers and by mono- and poly-synaptic inputs from Aδ- and C-fibers nociceptors. Another circuit links Aβ-fibers with lamina I NK1R− projection neurons through PKCγ+/SOM+ interneurons, central cells and SOM+ interneurons in outer lamina II. Information flow through this connection is controlled by feed-forward inhibition mediated by glycinergic and dynorphin-expressing interneurons.6,13 The Aβ-fiber subtypes that provide input to these circuits are unknown. Studies in humans14 and mice with impaired glutamate release from central synapses of C-LTMRs18 suggested that these afferents, which normally signal pleasant touch,10 might also signal mechanical allodynia. This hypothesis was, however, challenged by others who could not find differences in allodynia in mice lacking C-LTMRs11 and who were unable to induce tactile allodynia in patients lacking Aβ fibers.9 A possible explanation for this controversy is that C-LTMRs co-release the protein TAFA4, which counterbalances excitatory actions of glutamate.5 Thus, C-LTMR–specific loss of glutamatergic neurotransmission only,18 would result in a different phenotype than does the complete loss of C-LTMRs.11 C-fiber low-threshold mechanoreceptors project to lamina IIi and provide polysynaptic input to lamina I spinoparabrachial neurons,1 most of which express NK1R. They do not project to PKCγ+ neurons in the same lamina, which receive input from Aβ fibers.15 Putative C-LTMRs, as identified by means of conduction velocity and fiber diameter, also provide excitatory
drive onto GABAergic islet cells in lamina II, which regulate information flow from C-fiber nociceptors via central and vertical cells to NK1R+ projection neurons.12 Existence of this C-LTMR–driven pain-inhibiting connection is consistent with recent findings suggesting an analgesic effect of C-LTMR signaling,5 which is reduced during tactile allodynia.9 Whether there is a direct crosstalk between C-LTMR– and Aβ-fiber–processing circuits or whether these 2 pathways only converge at the level of lamina I projection neurons is still unclear. However, given the evidence for a role of both fiber types in mechanical allodynia and considering the columnar organization of the spinal projections of Aβ fibers and C-LTMRs from the same skin area,8 a functional connection between these circuits seems highly likely.
The authors have no conflicts of interest to declare.
16.
Institute of Pharmacology, Heidelberg University, 69120 Heidelberg, Germany
17.
* Corresponding author. Address: Institute of Pharmacology, Heidelberg University, 69120 Heidelberg, Germany E-mail address: stefan.lechner@pharma. uni-heidelberg.de (S. G. Lechner).
18.
A high resolution version version of this image is available online as Supplemental Digital Content at http://links.lww.com/PAIN/A38
220
A. Arcourt, S.G. Lechner • 156 (2015) 220–221
References 1. 2.
3. 4.
5.
6.
7. 8.
9.
10. 11.
12. 13.
14. 15.
19.
Andrew D. Quantitative characterization of low-threshold mechanoreceptor inputs to lamina I spinoparabrachial neurons in the rat. J Physiol 2010;588:117–24. Baba H, Ji RR, Kohno T, Moore KA, Ataka T, Wakai A, Okamoto M, Woolf CJ. Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn. Mol Cell Neurosci 2003;24:818–30. Campbell JN, Raja SN, Meyer RA, Mackinnon SE. Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 1988;32:89–94. Daniele CA, MacDermott AB. Low-threshold primary afferent drive onto GABAergic interneurons in the superficial dorsal horn of the mouse. J Neurosci 2009;29:686–95. Delfini MC, Mantilleri A, Gaillard S, Hao J, Reynders A, Malapert P, Alonso S, François A, Barrere C, Seal R, Landry M, Eschallier A, Alloui A, Bourinet E, Delmas P, Le Feuvre Y, Moqrich A. TAFA4, a chemokine-like protein, modulates injury-induced mechanical and chemical pain hypersensitivity in mice. Cell Rep 2013;5:378–88. Duan B, Cheng L, Bourane S, Britz O, Padilla C, Garcia-Campmany L, Krashes M, Knowlton W, Velasquez T, Ren X, Ross SE, Lowell BB, Wang Y, Goulding M, Ma Q. Identification of spinal circuits transmitting and gating mechanical pain. Cell 2014;159:1417-32. Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 1992;51:175–94. Li L, Rutlin M, Abraira VE, Cassidy C, Kus L, Gong S, Jankowski MP, Luo W, Heintz N, Koerber HR, Woodbury CJ, Ginty DD. The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 2011;147:1615–27. Liljencrantz J, Björnsdotter M, Morrison I, Bergstrand S, Ceko M, Seminowicz DA, Cole J, Bushnell MC, Olausson H. Altered C-tactile processing in human dynamic tactile allodynia. Pain 2013;154:227–34. Löken LS, Wessberg J, Morrison I, McGlone F, Olausson H. Coding of pleasant touch by unmyelinated afferents in humans. Nat Neurosci 2009;12:547–48. Lou S, Duan B, Vong L, Lowell BB, Ma Q. Runx1 controls terminal morphology and mechanosensitivity of VGLUT3-expressing C-mechanoreceptors. J Neurosci 2013;33:870–82. Lu Y, Perl ER. A specific inhibitory pathway between substantia gelatinosa neurons receiving direct C-fiber input. J Neurosci 2003;23:8752–758. Miraucourt LS, Moisset X, Dallel R, Voisin DL. Glycine inhibitory dysfunction induces a selectively dynamic, morphine-resistant, and neurokinin 1 receptor-independent mechanical allodynia. J Neurosci 2009;29:2519–27. Nagi SS, Rubin TK, Chelvanayagam DK, Macefield VG, Mahns DA. Allodynia mediated by C-tactile afferents in human hairy skin. J Physiol 2011;589:4065–75. Peirs C, Patil S, Bouali-Benazzouz R, Artola A, Landry M, Dallel R. Protein kinase C gamma interneurons in the rat medullary dorsal horn: distribution and synaptic inputs to these neurons, and subcellular localization of the enzyme. J Comp Neurol 2014;522:393–413. Sandkühler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 2009;89:707–58. Schoffnegger D, Ruscheweyh R, Sandkühler J. Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats. Pain 2008;135:300–10. Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 2009;462:651–55. Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 2010;11:823–36.
PAIN®
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
Projection neuron Excitatory interneuron Inhibitory interneuron
?
Morphologically and neurochemically undefined neurons yet undescribed ? Possible connection Glutamate TAFA4
February 2015 • Volume 156 • Number 2
© 2015 International Association for the Study of Pain (IASP). Permission for Use: For clinical, educational, or research purposes, reuse of this image is permitted for free with appropriate attribution to this article as the original source. For reproduction of the image for any commercial use, permission is needed from the Publisher.
www.painjournalonline.com
221
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
Peripheral and spinal circuits involved in mechanical allodynia Alice Arcourt, Stefan G. Lechner *
S
ensory information from nociceptors and touch receptors, such as Aβ-fiber mechanoreceptors and C-fiber low-threshold mechanoreceptors (C-LTMRs), is normally relayed and processed by separate neural circuits in the spinal cord.19 After nerve injury or inflammation, however, touch-related information is also relayed to nociceptive circuits in the superficial dorsal horn, which results in touch-evoked pain.16 Here, we depict the spinal circuits that facilitate this modality crosstalk and form the cellular basis of mechanical allodynia. A role of Aβ fibers in allodynia was originally proposed by human studies showing that compression block of Aβ fibers abolishes touch-evoked pain.3,7 Subsequent studies confirmed that after nerve injury, neurokinin-1 receptor (NK1R) expressing projection neurons in lamina I receive excitatory input from Aβ fibers via a preexisting polysynaptic connection that includes somatostatin (SOM) expressing interneurons, which also receive input from nociceptors.2,6,17 This connection is normally inhibited by dynorphin-/ GAD67-expressing GABAergic interneurons in lamina II,4,6 the activity of which is controlled by polysynaptic input from Aβ fibers and by mono- and poly-synaptic inputs from Aδ- and C-fibers nociceptors. Another circuit links Aβ-fibers with lamina I NK1R− projection neurons through PKCγ+/SOM+ interneurons, central cells and SOM+ interneurons in outer lamina II. Information flow through this connection is controlled by feed-forward inhibition mediated by glycinergic and dynorphin-expressing interneurons.6,13 The Aβ-fiber subtypes that provide input to these circuits are unknown. Studies in humans14 and mice with impaired glutamate release from central synapses of C-LTMRs18 suggested that these afferents, which normally signal pleasant touch,10 might also signal mechanical allodynia. This hypothesis was, however, challenged by others who could not find differences in allodynia in mice lacking C-LTMRs11 and who were unable to induce tactile allodynia in patients lacking Aβ fibers.9 A possible explanation for this controversy is that C-LTMRs co-release the protein TAFA4, which counterbalances excitatory actions of glutamate.5 Thus, C-LTMR–specific loss of glutamatergic neurotransmission only,18 would result in a different phenotype than does the complete loss of C-LTMRs.11 C-fiber low-threshold mechanoreceptors project to lamina IIi and provide polysynaptic input to lamina I spinoparabrachial neurons,1 most of which express NK1R. They do not project to PKCγ+ neurons in the same lamina, which receive input from Aβ fibers.15 Putative C-LTMRs, as identified by means of conduction velocity and fiber diameter, also provide excitatory
drive onto GABAergic islet cells in lamina II, which regulate information flow from C-fiber nociceptors via central and vertical cells to NK1R+ projection neurons.12 Existence of this C-LTMR–driven pain-inhibiting connection is consistent with recent findings suggesting an analgesic effect of C-LTMR signaling,5 which is reduced during tactile allodynia.9 Whether there is a direct crosstalk between C-LTMR– and Aβ-fiber–processing circuits or whether these 2 pathways only converge at the level of lamina I projection neurons is still unclear. However, given the evidence for a role of both fiber types in mechanical allodynia and considering the columnar organization of the spinal projections of Aβ fibers and C-LTMRs from the same skin area,8 a functional connection between these circuits seems highly likely.
The authors have no conflicts of interest to declare.
16.
Institute of Pharmacology, Heidelberg University, 69120 Heidelberg, Germany
17.
* Corresponding author. Address: Institute of Pharmacology, Heidelberg University, 69120 Heidelberg, Germany E-mail address: stefan.lechner@pharma. uni-heidelberg.de (S. G. Lechner).
18.
A high resolution version version of this image is available online as Supplemental Digital Content at http://links.lww.com/PAIN/A38
220
A. Arcourt, S.G. Lechner • 156 (2015) 220–221
References 1. 2.
3. 4.
5.
6.
7. 8.
9.
10. 11.
12. 13.
14. 15.
19.
Andrew D. Quantitative characterization of low-threshold mechanoreceptor inputs to lamina I spinoparabrachial neurons in the rat. J Physiol 2010;588:117–24. Baba H, Ji RR, Kohno T, Moore KA, Ataka T, Wakai A, Okamoto M, Woolf CJ. Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn. Mol Cell Neurosci 2003;24:818–30. Campbell JN, Raja SN, Meyer RA, Mackinnon SE. Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 1988;32:89–94. Daniele CA, MacDermott AB. Low-threshold primary afferent drive onto GABAergic interneurons in the superficial dorsal horn of the mouse. J Neurosci 2009;29:686–95. Delfini MC, Mantilleri A, Gaillard S, Hao J, Reynders A, Malapert P, Alonso S, François A, Barrere C, Seal R, Landry M, Eschallier A, Alloui A, Bourinet E, Delmas P, Le Feuvre Y, Moqrich A. TAFA4, a chemokine-like protein, modulates injury-induced mechanical and chemical pain hypersensitivity in mice. Cell Rep 2013;5:378–88. Duan B, Cheng L, Bourane S, Britz O, Padilla C, Garcia-Campmany L, Krashes M, Knowlton W, Velasquez T, Ren X, Ross SE, Lowell BB, Wang Y, Goulding M, Ma Q. Identification of spinal circuits transmitting and gating mechanical pain. Cell 2014;159:1417-32. Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 1992;51:175–94. Li L, Rutlin M, Abraira VE, Cassidy C, Kus L, Gong S, Jankowski MP, Luo W, Heintz N, Koerber HR, Woodbury CJ, Ginty DD. The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 2011;147:1615–27. Liljencrantz J, Björnsdotter M, Morrison I, Bergstrand S, Ceko M, Seminowicz DA, Cole J, Bushnell MC, Olausson H. Altered C-tactile processing in human dynamic tactile allodynia. Pain 2013;154:227–34. Löken LS, Wessberg J, Morrison I, McGlone F, Olausson H. Coding of pleasant touch by unmyelinated afferents in humans. Nat Neurosci 2009;12:547–48. Lou S, Duan B, Vong L, Lowell BB, Ma Q. Runx1 controls terminal morphology and mechanosensitivity of VGLUT3-expressing C-mechanoreceptors. J Neurosci 2013;33:870–82. Lu Y, Perl ER. A specific inhibitory pathway between substantia gelatinosa neurons receiving direct C-fiber input. J Neurosci 2003;23:8752–758. Miraucourt LS, Moisset X, Dallel R, Voisin DL. Glycine inhibitory dysfunction induces a selectively dynamic, morphine-resistant, and neurokinin 1 receptor-independent mechanical allodynia. J Neurosci 2009;29:2519–27. Nagi SS, Rubin TK, Chelvanayagam DK, Macefield VG, Mahns DA. Allodynia mediated by C-tactile afferents in human hairy skin. J Physiol 2011;589:4065–75. Peirs C, Patil S, Bouali-Benazzouz R, Artola A, Landry M, Dallel R. Protein kinase C gamma interneurons in the rat medullary dorsal horn: distribution and synaptic inputs to these neurons, and subcellular localization of the enzyme. J Comp Neurol 2014;522:393–413. Sandkühler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 2009;89:707–58. Schoffnegger D, Ruscheweyh R, Sandkühler J. Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats. Pain 2008;135:300–10. Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 2009;462:651–55. Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 2010;11:823–36.
PAIN®
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
Projection neuron Excitatory interneuron Inhibitory interneuron
?
Morphologically and neurochemically undefined neurons yet undescribed ? Possible connection Glutamate TAFA4
February 2015 • Volume 156 • Number 2
© 2015 International Association for the Study of Pain (IASP). Permission for Use: For clinical, educational, or research purposes, reuse of this image is permitted for free with appropriate attribution to this article as the original source. For reproduction of the image for any commercial use, permission is needed from the Publisher.
www.painjournalonline.com
221
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
