Intravenous recombinant cerebellin 1 treatment restores spinal glutamate delta 1 receptor signaling and mitigates chronic pain
Siddhesh S. Sabnis, Kishore Kumar S. Narasimhan, Poojashree B. Chettiar, Sukanya G. Gakare, Gajanan P. Shelkar, Devansh G. Asati, Shriti S. Thakur, Shashank M. Dravid- Pharmacology
Background and Purpose
Chronic pain remains a major clinical problem and there is a critical need to develop effective therapeutics. We recently demonstrated that glutamate delta 1 receptor (GluD1) and cerebellin 1 (Cbln1) are downregulated in the central amygdala (CeA) in inflammatory and neuropathic pain. Importantly, we found that administering Cbln1 intracerebroventricularly (ICV) or in CeA once, normalizes GluD1 and reduces AMPA receptor expression resulting in lasting (7‐10 days) pain relief. Unlike many CNS‐targeting biologics, Cbln1 structure suggests potential blood‐brain‐barrier penetration. Hence, in this study we tested whether systemic administration of Cbln1 provides analgesic effect via CNS mechanism.
Experimental Approach
Analgesic effect of intravenously (IV) administered recombinant Cbln1 was assessed in Complete Freund's Adjuvant (CFA) inflammatory pain model. GluD1 knockout and mutant form of Cbln1 were used.
Key Results
A single IV injection of Cbln1 mitigated nocifensive and averse behavior in both inflammatory and neuropathic pain models. This effect of Cbln1 was dependent on GluD1 and required binding to GluD1 amino terminal domain. Time course of analgesic effect was similar to previously reported ICV and intra‐CeA injection. Downregulation of GluD1 in both spinal cord and CeA was observed in the inflammatory pain model, however, GluD1 expression in spinal cord but not CeA was partially normalized by IV Cbln1. Importantly, recombinant Cbln1 was detected in the synaptoneurosomes in spinal cord but not in RCeA.
Conclusions and Implications
Together, our study demonstrates a novel mechanism by which systemic Cbln1 produces analgesia potentially by central mechanism involving normalization of spinal cord GluD1 signaling.