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MrgprdCre lineage neurons mediate optogenetic allodynia through an emergent polysynaptic circuit. Pain 2021 Jul 01;162(7):2120-2131

Date

06/16/2021

Pubmed ID

34130311

Pubmed Central ID

PMC8206522

DOI

10.1097/j.pain.0000000000002227

Scopus ID

2-s2.0-85108247993 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

Most cutaneous C fibers, including both peptidergic and nonpeptidergic subtypes, are presumed to be nociceptors and respond to noxious input in a graded manner. However, mechanically sensitive, nonpeptidergic C fibers also respond to mechanical input in the innocuous range, so the degree to which they contribute to nociception remains unclear. To address this gap, we investigated the function of nonpeptidergic afferents using the MrgprdCre allele. In real-time place aversion studies, we found that low-frequency optogenetic activation of MrgrpdCre lineage neurons was not aversive in naive mice but became aversive after spared nerve injury (SNI). To address the underlying mechanisms of this allodynia, we recorded responses from lamina I spinoparabrachial (SPB) neurons using the semi-intact ex vivo preparation. After SNI, innocuous brushing of the skin gave rise to abnormal activity in lamina I SPB neurons, consisting of an increase in the proportion of recorded neurons that responded with excitatory postsynaptic potentials or action potentials. This increase was likely due, at least in part, to an increase in the proportion of lamina I SPB neurons that received input on optogenetic activation of MrgprdCre lineage neurons. Intriguingly, in SPB neurons, there was a significant increase in the excitatory postsynaptic current latency from MrgprdCre lineage input after SNI, consistent with the possibility that the greater activation post-SNI could be due to the recruitment of a new polysynaptic circuit. Together, our findings suggest that MrgprdCre lineage neurons can provide mechanical input to the dorsal horn that is nonnoxious before injury but becomes noxious afterwards because of the engagement of a previously silent polysynaptic circuit in the dorsal horn.

Author List

Warwick C, Cassidy C, Hachisuka J, Wright MC, Baumbauer KM, Adelman PC, Lee KH, Smith KM, Sheahan TD, Ross SE, Koerber HR

Author

Tayler D. Sheahan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Hyperalgesia
Mice
Neurons
Nociceptors
Optogenetics
Spinal Cord Dorsal Horn