Figure 1. Genes Involved in Pain Perception and Modulation. Noxious stimuli are detected by primary afferent neurons innervating the skin, muscle, and viscera. The cell bodies of these damage-sensing neurons (nociceptors) are found in dorsal root ganglia, except for neurons innervating craniofacial tissues, which have cell bodies in the trigeminal ganglia. Nociceptors are commonly divided into three groups: peptidergic (blue, NGF- responsive) and nonpeptidergic (black, GDNF-responsive) unmyelinated C-fibres, and myelinated Ad-fibres (red, NGF-responsive). Gene expression profiles differ between these groups, with functional distinctions (reviewed in [62]). Specialised receptors, expressed in the peripheral termini of these neurons, allow noxious stimuli to be transduced into electrical impulses. While the majority of nociceptors are polymodal (they can detect a variety of noxious stimuli), specific receptors exist for each stimulus modality. The receptors for certain modalities, including mechanical and heat damage, are currently unidentified, although several promising candidates have been proposed. In particular, specific TRP channels appear to be involved in transduction of several stimulus modalities (e.g., [56,57,63,64]). The local membrane depolarisation generated by stimulus transduction is transmitted along the axon by voltage-gated sodium channels, some of which are expressed specifically in nociceptors. The channels NaV1.7 (SCN9A) and NaV1.8 (SCN10A) have both been shown to play an important role in nociceptive transmission [6,7,11]. Transmission is modulated by the actions of potassium channels, which generally act to reduce excitability. Regulation of spike frequency by potassium channels has also been reported. The sensitivity of both transduction and action potential transmission by nociceptors can be altered by inflammatory and other mediators, released by immune system cells and damaged neurons. This modulation is an important component of inflammatory hyperalgesia and neuropathic allodynia, in which neuronal sensitivity is greatly increased. Nociceptors terminate in laminae 1 (Ad-fibres) and 2 (C-fibres) of the spinal cord dorsal horn, forming synapses with nociceptive-specific spinal projection neurons. Some also synapse with wide dynamic range projection neurons in lamina 5, while light touch neurons synapse in deeper laminae. Synaptic transmission occurs through NMDA, AMPA, and kainate receptors, in addition to neuropeptide and proton-mediated transmission. Neurotransmitter release is controlled by voltage-gated Ca2+ channels in the presynaptic membrane. Regulation of synaptic strength is achieved by many mechanisms, including long-term potentiation, whereby repeated activity within a frequency range results PLoS Genetics | www.plosgenetics.org 2 July 2008 | Volume 4 | Issue 7 | e1000086