A large number of chemical mediators produced at the site of tissue injury and inflammation are capable of promoting the excitation and sensitization of nociceptors. Inflammatory mediators such as bradykinin, histamine, serotonin (5-HT), and prostaglandin E₂ (PGE₂), have been shown to produce both excitation and mechanical sensitization of somatic (87) and meningeal nociceptors (22,89). Other inflammatory mediators known to promote peripheral sensitization are pro-inflammatory cytokines, most notably interleukin (IL)-1, IL-6, and IL-8 and tumor necrosis factor-α (TNF-α) (56,77). These mediators are believed to promote nociceptor sensitization through the endogenous release of eicosanoids and sympathetic amines (77). Additional inflammatory mediators proposed to promote peripheral sensitization include protons, proteases, and nitric oxide. Increased levels of protons (acidic pH) found in inflamed tissues, produce not only activation and sensitization of meningeal nociceptors (89), but also enhances the effects of other inflammatory mediators (87).
Inflammatory proteases, especially tryptase and trypsins, activate protease-activated receptors (PARs) on nociceptors, most notably PAR-2 (33). Nitric oxide has been shown to produce local inflammation within the meninges (74), sensitize meningeal nociceptors (53), and induce headache or migraine in patients (68). Interestingly, release of nitric oxide from the endothelium can also be induced by bradykinin and histamine.

Most sensitizing agents activate receptors that are coupled to second messenger cascades that, in turn, modulate voltage-gated ion channels. Other potential targets for the actions of sensitizing agents on nociceptors may also include direct action on sensory transduction elements. Mechanical and thermal sensitivity can be modulated independently in individual nociceptors, suggesting the existence of separate, possibly multiple, transduction mechanisms (5,70). For example, increased thermal skin sensitivity can be mediated by the transient receptor potential ion channel 1, a transducer of noxious heat (71,95) when its threshold is lowered by bradykinin, PAR-2 agonist, and protons (20,76,91). The mechanism underlying increased mechanical sensitivity remains largely unknown; transducers of noxious mechanical stimuli are yet to be identified.

Peripheral sensitization can also be promoted by changes in the properties of voltage-gated ion channels, such as the TTX-resistant (TTX-R) sodium channel. Inflammatory agents such as PGE₂ and 5-HT are thought to sensitize sensory neurons by modulating TTX-R sodium currents (30) through activation of the cyclic adenosine monophosphate (cAMP)-PKA second messenger cascade (31). Such action is also likely to be involved in sensitization of mechanosensitive meningeal nociceptors as they express the TTX-R channels (88) and are sensitized by the cAMP-PKA cascade (52). The cAMP-PKA is also likely to be involved in mechanical sensitization through the suppression of the sustained (delayed rectifier) outward K⁺ current that is thought to modulate the firing threshold (27,28) and the enhancement of I_h, the hyperpolarizationactivated cation current that is thought to facilitate repetitive firing (39). Another second messenger cascade that may also promote mechanical sensitization is the cyclic guanosine monophosphate (cGMP)-PKG cascade that is activated by nitric oxide. As already noted, the sensitizing action of nitric oxide on meningeal nociceptors could also involve the activation of this cascade probably through the facilitation of Ca⁺²-activated potassium (BK) channels (47).

The proximate factors that cause local release of sensitizing chemicals during migraine remain unknown. One presumed factor is cortical spreading depression—a slowly propagating wave of neural inhibition (and excitation)
associated with extracellular release of excitatory agents such as potassium and glutamate. Bolay et al. (10) have recently shown that cortical spreading depression activates the trigeminovascular system. One of the potential consequences of sensory fiber activation is the release of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) from the peripheral terminals of meningeal nociceptors which, in turn, promotes vasodilatation and plasma extravasation (17,49,84). CGRP and SP are thought to sensitize nociceptors indirectly by inducing the release of sensitizing inflammatory mediators such as histamine, 5HT, BK, TNF-α, and nitric oxide from other immune cells, especially mast cells, in a process known as mast cell degranulation (75,92, 108).

Most of other triggering factors are, however, likely to be extrinsic to the brain and may include increased stress level, change in hormone levels, and certain types of food. Such processes may directly or indirectly cause the release of excitatory and sensitizing molecules by promoting activation of inflammatory cells in the meninges, most notably mast cells (94), that are capable of releasing a large
number of excitatory and sensitizing mediators including histamine, nitric oxide, prostaglandins, and cytokines.

Central sensitization in somatosensory pain pathways was first discovered in the rat spinal cord, where it was shown to have a role in producing postinjury pain hypersensitivity (102), and later documented in several animal models and in humans (35,48,57,73,85,96). Central sensitization refers to a condition where nociceptive neurons in the dorsal horn of the spinal cord exhibit increased excitability, increased synaptic strength, and enlargement of their receptive fields beyond the original site of inflammation or injury (63,103,104). Central sensitization is triggered by sensory input arriving from sensitized nociceptors that supply the affected site. Once initiated, the sensitization of the central neurons may remain dependent on incoming input (activity dependent) or become self-sufficient altogether (activity independent). Sensitized dorsal horn nociceptors become responsive to innocuous (previously subthreshold) sensory signals that arrive from areas outside the affected site, resulting in expansion of their receptive fields. Accordingly, central sensitization is manifested clinically as decreased pain threshold and exaggerated pain response referred outside the original pain site.