Nociceptive neurons of dorsal root and trigeminal ganglia control neurogenic inflammation and pain transmission. The peripheral projections of nociceptors express G protein-coupled receptors (GPCRs) and transient receptor potential (TRPs) ion channels, which permit neurons to detect diverse chemical and physical stimuli that are generated during injury/inflammation. The peripheral endings of activated nociceptors release substance P and calcitonin gene-related peptide, which stimulate plasma extravasation, granulocyte infiltration and hyperemia (neurogenic inflammation). Activated nociceptors can transmit action potentials centrally, which stimulates the release of neuropeptides in the dorsal horn of the spinal cord that transmit pain. The assembly of multi-protein signaling complexes within nociceptors, comprising GPCRs, TRPs and scaffolding proteins such as β-arrestins, ensures the efficient and selective activation of nociceptors, and promotes the bidirectional functional interactions between GPCRs and TRPs. For example, proteases that are generated during injury/inflammation signal to nociceptors by cleaving protease-activated receptor-2 (PAR₂). PAR₂ sensitizes and activates TRPV1, TRPV4 and TRPA1, which amplify protease signaling. Thus, PAR₂ activates TRPV4 by mechanisms that include generation of endogenous agonists and which require channel phosphorylation (Y110), leading to sustained inflammation and pain. Activated TRP channels can in turn desensitize PAR₂, representing a mechanism of bidirectional communication that terminates protease signaling. β-arrestins interact with agonist-occupied GPCRs at the cell-surface to mediate receptor desensitization and endocytosis. Analysis of PAR₂/β-arrestin/TRP channel interactions using bioluminescence resonance energy transfer and co-immunoprecipitation indicates that PAR₂ or TRP channel activation triggers the assembly of PAR₂, β-arrestin and TRP complexes. Such complexes could provide a matrix for the efficient bi-directional communication between PARs and TRP channels, allowing PARs to couple to TRPs, and TRPs to desensitize PARs. Unraveling the complexity and functions of these complexes can provide new insights into neurogenic inflammation and nociception, and drugs that disrupt complex assembly may have therapeutic potential.