Unique features of sensory neuron subtypes are manifest by their distinct physiological and pathophysiological functions. Using patch-clamp electrophysiology, Ca 2+ imaging, CGRP release assay from tissues, protein biochemistry approaches and behavioral physiology on pain models, this study demonstrates the diversity of sensory neuron pathophysiology is due in part to subtype-dependent sensitization of TRPV1 and TRPA1. Differential sensitization is influenced by distinct expression of inflammatory mediators, such as prostaglandin E 2 (PGE 2), bradykinin (BK) and nerve growth factor (NGF) as well as multiple kinases, including protein kinase A (PKA) and C (PKC). However, the co-expression and interaction of TRPA1 with TRPV1 proved to be most critical for differential sensitization of sensory neurons. We identified N-and C-terminal domains on TRPV1 responsible for TRPA1-TRPV1 (A1–V1) complex formation. Ablation of A1–V1 complex with dominant negative peptides against these domains substantially reduced sensitization of TRPA1, as well as BK-and CFA-induced hypersensitivity. These data indicate that often occurring TRP channel complexes regulate diversity in neuronal sensitization and may provide a therapeutic target for many neuro-inflammatory pain conditions.