Heat, but not mechanical hyperalgesia, following adrenergic injections in normal human skin

The development of adrenergic sensitivity in nociceptors has been suggested as a mechanism of neuropathic pain. We sought to determine if nociceptors in the skin of normal subjects exhibit adrenergic sensitivity. We investiga ted the effects of intradermal administration of norepinephrine, phenylephr ine, and brimonidine on heat pain sensitivity. Norepinephrine and phenyleph rine (in concentrations ranging from 0.1 to 10 muM by factors of 10), brimo nidine (at 0.01-1 muM), and saline were injected (30 mul volume) in a rando m, double-blind manner to different sites on the volar surface of the forea rm in ten subjects. Before and after the injections, heat testing was perfo rmed with a noncontact laser thermal stimulator. Heat pain threshold was me asured by means of a 'Marstock' technique in which subjects pressed a react ion time key when they perceived that a slowly increasing heat stimulus (1 degreesC/s ramp from a 36 degreesC base) was painful. In addition, the subj ects used magnitude estimation techniques to rate the intensity of pain to a suprathreshold heat stimulus (47 degreesC, 2 s). Mechanical testing was d one using 200-mum diameter probes attached to calibrated weights that provi ded forces over the range of 16-512 mN. The intradermal injections of norep inephrine, phenylephrine and brimonidine produced little evoked pain. Howev er, a dose-dependant decrease in heat pain threshold, but not mechanical pa in threshold, was observed. At the highest drug dose injected, ail three ad renergic compounds produced a significant decrease in heat pain threshold c ompared to the saline injection. A significant increase in response to the suprathreshold heat stimulus was also found. One possible explanation for t his apparent heat hyperalgesia is that the decrease in perfusion due to the localized vasoconstriction may alter the heat response. However, in contro l studies we found that the non-adrenergic vasoconstrictors, angiotensin II and vasopressin did not produce heat hyperalgesia at doses that produced c omparable decreases in blood flow. In addition, occlusion of blood flow wit h a blood pressure cuff did not lead to heat hyperalgesia. Thus, the heat h yperalgesia observed with the adrenergic agonists is not due to a decrease in perfusion associated with the injection. These results indicate that alp ha (1)- and alpha (2)-adrenoceptor-mediated mechanisms may play a role in s ensitization of nociceptors to heat stimuli in normal skin. (C) 2001 Intern ational Association for the Study of Pain. Published by Elsevier Science B. V. All rights reserved.