Is thermal nociception only sensed by the capsaicin receptor, TRPV1?

Mammalian heat pain perception is well documented as a molecular event in the primary afferent neurons expressing TRPV1. Six types of thermo-TRPs were found, i.e., TRPV1-4, TRPM8 and TRPA1. The former TRPV1, 2 and TRPV3, 4 are sensitive to noxious heat and warmth, and the latter two are sensitive to cool or cold, respectively. We attempted to provide a hypothesis to explain the paradox in which TRPV1 knockout mice and capsaicin-pretreated mice with severe loss of small dorsal root ganglion (DRG) neurons behave normally to noxious heat. From the general view that TRPV1 is preferentially expressed in C-fibers responding to a moderate thermal threshold (> 43A degrees C) and TRPV2 in A delta-fibers to high threshold temperatures (> 52A degrees C), the above phenomenon is perplexing. Woodbury et al. (J Neurosci 24:6410-6415, 2004) offered two pain transduction mechanisms, one being TRPV1/2-independent and the other TRPV1-dependent. The former detects noxious heat under normal conditions without the presence of TRPV1 or TRPV2, and the latter requires TRPV1 under pathophysiological conditions. Unidentified isolectin B4 (IB4)-positive but TRPV1-negative small neurons with a higher noxious heat threshold are feasible, because a spliced isoform of TRPV1 responsive to noxious heat (47A degrees C) but not responsive to either proton or capsaicin is present in human and rat sensory neurons. Thus, the IB4-positive but TRPV1-negative small sensory neurons must have a crucial role in the noxious heat response.