Study of peripheral mechanism of hyperalgesia in neuropathic pain

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We have reported that sympathomimetics excites cutaneous polymodal receptors (CPRs) in some pathological conditions. However, it remains obscure whether sympathetic action augments the CPR responses to other types of stimulus. To clarify this issue, the effects of norepinephrine (NE) on the heat and bradykinin (BK) responses of CPRs were studied using skin-saphenous nerve in vitro preparation. Under deep anesthesia, the saphenous nerve in continuity with the hind paw skin of normal SD rats was sabcutaneously dissected and excised. Receptive fields of identified single CPR units were superfused with chemical solutions or ramp-heated at the corium side. There was a large inter-individual variability in pattern and magnitude of the BK (1-10 uM) response, and a marked tachyphylaxis upon repeated BK superfusion (10-min interval) was observed. NE (1-10 uM) by itself did not excite CPRs before BK or heat stimulations. In contrast, after a few trials of BK or heat, some CPR units were excited by NE.NE (1-10 uM) sensitized the BK responses, while it suppressed the heat responses regardless of the presence of NE-induced excitation. These results suggest different mechanisms of NE-modification on BK and heat responses of CPRs.Next we have focused on the mechanism of NE-sensitization on BK response and determined if an a_2-adrenoceptor mediates this effect. Receptive fields of identified single CPRs were superfused with BK (1-10 uM) at the corium side for 60 sec with 10-mm intervals. BK responses increased after NE application, and this effect lasted till the 2nd.BK response after NE application (N=10). NE combined with a_2-antagonists, yohinibine (1-10 uM) or CH-38083 (1-10 uM), however, failed to sensitize the BK responses (N=7). These results suggest that NE-induced sensitization of BK response was mediated through a_2-adrenoceptors.