TY - JOUR
T1 - Chronicling changes in the somatosensory neurons after peripheral nerve injury
AU - Raghuraman, Shrinivasan
AU - Xie, Jennifer Y.
AU - Giacobassi, Mario J.
AU - Tun, Jortan O.
AU - Chase, Kevin
AU - Lu, Dong
AU - Teichert, Russell W.
AU - Porreca, Frank
AU - Olivera, Baldomero M.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Jeff Woodbury for helpful comments and discussions in drafting the manuscript. We also thank Dr. Rajesh Khanna for providing resources to complete experiments at The University of Arizona. This work was supported by Department of Defense PR Grant 161686, “Novel strategies for accelerating non-opioid drug discovery,” and National Institute of General Medical Sciences Grant GM 48677, “Conus Peptides and Their Receptor Targets: Towards Constellation Pharmacology” (to B.M.O.). This work is based in part on the PhD dissertation of S.R.
Funding Information:
We thank Dr. Jeff Woodbury for helpful comments and discussions in drafting the manuscript. We also thank Dr. Rajesh Khanna for providing resources to complete experiments at The University of Arizona. This work was supported by Department of Defense PR Grant 161686, "Novel strategies for accelerating non-opioid drug discovery, " and National Institute of General Medical Sciences Grant GM 48677, "Conus Peptides and Their Receptor Targets: Towards Constellation Pharmacology" (to B.M.O.). This work is based in part on the PhD dissertation of S.R.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/10/20
Y1 - 2020/10/20
N2 - Current drug discovery efforts focus on identifying lead compounds acting on a molecular target associated with an established pathological state. Concerted molecular changes that occur in specific cell types during disease progression have generally not been identified. Here, we used constellation pharmacology to investigate rat dorsal root ganglion neurons using two models of peripheral nerve injury: chronic constriction injury (CCI) and spinal nerve ligation (SNL). In these well-established models of neuropathic pain, we show that the onset of chronic pain is accompanied by a dramatic, previously unreported increase in the number of bradykinin-responsive neurons, with larger increases observed after SNL relative to CCI. To define the neurons with altered expression, we charted the temporal course of molecular changes following 1, 3, 6, and 14 d after SNL injury and demonstrated that specific molecular changes have different time courses during the progression to a pain state. In particular, ATP receptors upregulated on day 1 postinjury, whereas the increase in bradykinin receptors was gradual after day 3 postinjury. We specifically tracked changes in two subsets of neurons: peptidergic and nonpeptidergic nociceptors. Significant increases occurred in ATP responses in nAChR-expressing isolectin B4+ nonpeptidergic neurons 1 d postinjury, whereas peptidergic neurons did not display any significant change. We propose that remodeling of ion channels and receptors occurs in a concerted and cell-specific manner, resulting in the appearance of bradykinin-responsive neuronal subclasses that are relevant to chronic pain.
AB - Current drug discovery efforts focus on identifying lead compounds acting on a molecular target associated with an established pathological state. Concerted molecular changes that occur in specific cell types during disease progression have generally not been identified. Here, we used constellation pharmacology to investigate rat dorsal root ganglion neurons using two models of peripheral nerve injury: chronic constriction injury (CCI) and spinal nerve ligation (SNL). In these well-established models of neuropathic pain, we show that the onset of chronic pain is accompanied by a dramatic, previously unreported increase in the number of bradykinin-responsive neurons, with larger increases observed after SNL relative to CCI. To define the neurons with altered expression, we charted the temporal course of molecular changes following 1, 3, 6, and 14 d after SNL injury and demonstrated that specific molecular changes have different time courses during the progression to a pain state. In particular, ATP receptors upregulated on day 1 postinjury, whereas the increase in bradykinin receptors was gradual after day 3 postinjury. We specifically tracked changes in two subsets of neurons: peptidergic and nonpeptidergic nociceptors. Significant increases occurred in ATP responses in nAChR-expressing isolectin B4+ nonpeptidergic neurons 1 d postinjury, whereas peptidergic neurons did not display any significant change. We propose that remodeling of ion channels and receptors occurs in a concerted and cell-specific manner, resulting in the appearance of bradykinin-responsive neuronal subclasses that are relevant to chronic pain.
KW - Bradykinin
KW - Cell types
KW - Constellation pharmacology
KW - Dorsal root ganglion
KW - Nerve injury
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U2 - 10.1073/pnas.1922618117
DO - 10.1073/pnas.1922618117
M3 - Article
C2 - 33020310
AN - SCOPUS:85093869903
SN - 0027-8424
VL - 117
SP - 26414
EP - 26421
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -