Tyramine Facilitates Peripheral Pain Sensitivity In A Manner That Depends On The PKC_θ Pathway

Objective: To investigate the possible mechanisms of TAAR1(Trace amine-associated receptor 1) involved in the inflammatory pain of trigeminal nerve; To study the mechanisms of TAAR1 receptor-mediated membranal superexcitation of trigeminal ganglion neurons in mice.Methods: 1)Molecular Biology methods(mainly including western blot 、immunofluorescence) were used to test the expression of TAAR1 receptor of the trigeminal ganglion neurons in mice. 2)The whole-cell patch clamp recording was used to investigate the effect of TAAR1 activated by its endogenous ligand(tyramine) on neuronal excitability in small TG neurons and the signaling pathways. 3)Behavior tests(von Frey test) were used to detect the effects of TAAR1 in trigeminal neuralgia.Results: In the present study, we found that :1) TAAR1 existed in the TG neurons on protein level(tested by western blot, immunofluorescence). 2) Inflammation by CFA injection in trigeminal nerve increases TAAR1 expression. 3) TAAR1 activated by its endogenous ligand(tyramine) increased excitability of TG. 4) The effect of enhanced excitability after administration of tyramine used to activate TAAR1 was blocked by TAAR1 blocker(EPPTB), A-type potassium current specific blocker(4- AP), PKCθ blocker(PKCθ inhibitor protein). 5) Administration of 0.1μM tyramine in the trigeminal nerve produced hyperalgesia significantly during 20 min to 90 min, however, these effect can be inhibited by TAAR1 blocker(EPPTB), PKCθ blocker(PKCθ inhibitor protein), but not by PKA blockers(KT5720).In addition, TAAR1 receptor blockers(EPPTB) can alleviate pain induced by trigeminal neuralgia in mice at 30 min after treatment.Conclusions: These results together showed that increased TAAR1 expression of TG was contributed to the trigeminal neuralgia in mice.Activated TAAR1 receptor enhanced excitability of small trigeminal ganglion neurons in mice via PKCθ pathway which can change A-type potassium current.