Analysis of peripheral mechanism for cold-induced aggravation of pain in inflammation and nerve injury models

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To clarify the peripheral mechanism for cold-induced aggravation of pain in inflammation and nerve injury models, following experiments were carried out.1) We examined cold sensitivity of cultured dorsal root ganglion (DRG) neurons obtained from adjuvant-monoarthritic rats using Ca-imaging technique. The percentage of neurons responding to cold down to 10℃ was about 80% both in normal and inflamed animals. Percentage of neurons sensitive to mustard oil (MO, a TRPA1 agonist) was 56% in inflamed animals, much higher than 20% in normal group. The great majority of neurons sensitive to menthol (MT, a TRPM8 agonist) was also sensitive to MO. The threshold temperature to cooling of MO-sensitive and MT-insensitive neurons was 18.4℃ in inflamed group, higher than 14.0℃ in the normal group.2) We demonstrated the temperature dependency of acid sensitivity in cultured DRG neurons.3) Mechanical hyperalgesia in adjuvant-monoarthritic rats was worsened by exposure to cold (15℃).4) To know the basic mechanism for inflammatory hyperalgesia, we examined effects of ATP on C-fiber receptors. ATP suppressed through P2X receptors the heat response of nociceptors at a low concentration (10μM), while it facilitated the heat response through P2Y receptors at a high concentration (1mM).5) To clarify the interaction of various inflammatory mediators, we examined effects of bradykinin (BK) and noradrenaline (NA) on single C-fiber receptor activities. BK-induced discharges were enhanced by pretreatment with NA, vice versa. This result suggests that despite of its weak excitatory effect by itself, NA in co-operation with other mediators induces larger effects.6) We induced muscle mechanical hyperalgesia by lengthening contraction of the dorsi-flexors of the lower hindpaw. We demonstrated that the mechanical sensitivity of muscle C-fiber receptors was increased in this hyperalgesic muscle.