Caveats and Qualifications

While it is true that, in general terms, sensitization will involve common processes such as increases in inward currents and/or excitatory input and decreases in outward currents or inhibitory input, it is also true that the exact nature of these processes are influenced by a number of important factors. Several of these factors have been discussed above. These include (i) timing and or duration of an injury, as the underlying mechanisms mediating pain can and do change over the time course of an injury (130), (ii) history of the organism, as previous injury (22), as well as developmental experiences (23) impact the response to subsequent injury, (iii) the type of injury, as the response to nerve injury (155) may be distinct from that associated with inflammation (156), and (iv) site of injury, which may not only influence second-messenger pathways utilized, but the relative involvement of various ion channels (120).

There are at least two additional factors that also appear to influence mechanisms of sensitization. First, there is sex and/or gonadal status of the organism. While debate continues over whether there is a difference between men and women with respect to pain threshold and pain tolerance (157-159), there is little debate over the question about whether there is a sex difference in the expression of persistent, particularly inflammatory, pain. Women, in general, are more likely to suffer from inflammatory pain that is often more intense and longer lasting than that in men (159-161). While there are a number of mechanisms that may contribute to this difference, evidence from both clinical and preclinical studies suggests that gonadal hormones, in particular estrogen, may be a critical factor. Its mechanisms of action are complex, as estrogen has been shown to influence structures relevant to nociception throughout the body. Timing, with respect to estrogen cycling or the sustained application of estrogen (as in the case of hormone replacement therapy), site of action, and dependent measures of nociception all appear to be important factors when assessing the impact of estrogen on specific aspects of nociceptive processing (120).

A second factor that appears to influence the response to injury and pain, if not sensitization, is genetic background. Mutations in specific genes have recently been linked to two pain disorders: erythmalgia (162) and hemiplegic migraine (163). More subtle changes in specific genes have also been shown to influence the response to noxious stimulation and analgesics and the likelihood of developing a pain condition. These include single-nucleotide polymorphisms in genes encoding the m-opioid receptor (164), an isoform of cytochrome P450 (165), melanocortin receptor-1 (166), and a catalytic enzyme catechol-O-methyl transferase (COMT) (167). Specific haplotype blocks of COMT correlate with both pain tolerance and threshold ratings and increased likelihood of developing a pain syndrome (168).

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