GENETIC AND PHARMACOLOGICAL BLOCKAGE OF THE TISSUE PLASMINOGEN ACTIVATOR (TPA)-DEPENDENT N-METHYL-D-ASPARTATE RECEPTOR (NMDAR) SIGNALING REDUCES PAIN

N-Methyl-D-Aspartate receptors (NMDARs) are known for their role in synaptic plasticity and central sensitization of pain. Therefore, NMDAR antagonists represent an interesting therapeutic target for pain management. Studies have shown that tissue Plasminogen Activator (tPA), a well-known neuronal and endothelial serine protease involved in long-term potentiation and neurovascular coupling, was reported to modulate NMDAR signaling. Here, we examined the responses to acute pain in mice using both genetical and pharmacological approaches to knock-down tPA-NMDAR signaling, a knock-in of Lysine (K) 178 into Alanine (A) (K178A) of the GluN1 subunit of NMDAR and a blocking monoclonal antibody (Glunomab). We then investigated the impact of these specific blockages on a set of pain behaviors, compared with gold standard analgesic drugs.
We demonstrate that both the genetic (KI K178A mice) and pharmacological blockages of tPA_NMDAR lead to analgesia in the context of acute thermal and mechanical pain. Although paracetamol administration induces analgesia in KI(K178A) mice, morphine injections had no effect. Interestingly, a single administration of Glunomab led to a prolonged analgesia, up to 4 days.
Taken together, these results reveal that tPA-NMDAR signaling plays a key role in pain and that targeting this pathway may be a solution for the future of pain care.