Cold inhibits pain through activating the cold sensing TRPM8 ion channel, and has been widely used as an approach to pain relief. However, TRPM8 is inhibited during inflammation leading to disinhibition of the analgesic effect of cold, contributing to aggravated pain. Inflammatory mediators such as bradykinin and histamine inhibit TRPM8 through acting on Gαq-protein coupled receptors (GPCRs). Both activated Gαq and the downstream hydrolysis of the membrane lipid phosphatidylinositol 4, 5-bisphosphate (PIP2) inhibit TRPM8. However, how Gαq directly gates TRPM8 and the relative role of Gαq gating and PIP2 signaling in TRPM8 mediated cold signaling remain elusive. Here, we took advantage of Gαq knockout mice in which phospholipase Cβ (PLCβ)-PIP2 signaling is intact carried by Gα11, thus allowing for discrimination between Gαq gating and PIP2 signaling in TRPM8 modulation. Combined with cell-attached electrophysiological recordings, we show that direct Gαq gating is essential for the basal cold sensitivity of TRPM8, and is also the sole mechanism for TRPM8 inhibition caused by bradykinin in native sensory neurons without the involvement of PLCβ-PIP2 signaling or Gα11 in this process, because deleting Gαq markedly enhanced TRPM8-mediated firing evoked by cold, and abolished the inhibitory effect of bradykinin on TRPM8-mediated firing responses in sensory neurons, while sparing PLCβ-PIP2 signaling. We then identified three key arginine residues in the N-terminal melastain homology regions (MHRs) of TRPM8 as Gαq gating sites using protein binding assays and mutagenesis. Neutralization of these positively charged residues dramatically enhanced the sensitivity and voltage-dependent gating of TRPM8, and completely abolished TRPM8 inhibition by both Gαq and bradykinin without affecting the channel sensitivity to PIP2. Interestingly, TRPM8 binding to Gαq also reciprocally competes with Gαq binding and coupling to PLCβ-PIP2, leading to reduced PIP2 hydrolysis and signaling based on live cell imaging and functional assays. Furthermore, the bradykinin receptor B2R also binds to TRPM8 rendering TRPM8 insensitive to PIP2 depletion. Thus, TRPM8 and B2R/Gαq form a bidirectional signaling complex that act together to opt Gαq gating rather than PIP2 signaling as a primary means for TRPM8 inhibition during inflammation. These findings implicate a critical role for the N-terminal MHRs in TRPM8 gating and cold signaling. The revealed Gαq gating sites represent interesting targets for TRPM8 drug discovery.