Intra-articular AAV-PHP- S mediated chemogenetic targeting of knee-innervating DRG neurons alleviates inflammatory pain in mice
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S Chakrabarti, LA Pattison, B Doleschall, RH Rickman et al

Department of Pharmacology, University of Cambridge, UK.


Joint pain is the major clinical symptom of arthritis that affects millions of people. Controlling the excitability of knee-innervating dorsal root ganglion (DRG) neurons (knee neurons) by delivering artificial receptors to regulate neuronal activity could potentially provide pain relief. Gene delivery into DRG neurons by injection of adeno-associated virus (AAV) into peripheral organs has had limited success because of the large anatomical distances involved in the periphery. Here we show that the newly engineered serotype, AAV-PHP.S, can deliver functional excitatory (Gq) and inhibitory (Gi) designer receptors activated by designer drugs (DREADDs) into knee neurons of mice to bidirectionally control excitability in vitro, i.e., activated Gq-DREADD increased neuronal excitability while Gi-DREADD decreased neuronal excitability. In vivo, short-term Gq-DREADD activation caused a deficit in motor coordination while Gi-DREADD activation was able to alleviate complete Freund’s adjuvant mediated knee inflammation-induced deficits in digging behavior, a measure of spontaneous pain associated with well-being. This approach may be utilized in translational pain research for peripheral organ specific pain relief.

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