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 investigated the effects of intradermal administration of
norepinephrine,
phenylephrine, and
brimonidine on heat
pain sensitivity.
Norepinephrine and
phenylephrine (in concentrations ranging from 0.1 to 10 microM by factors of 10),
brimonidine (at 0.01-1 microM), and saline were injected (30 microl volume) in a random, double-blind manner to different sites on the volar surface of the forearm in ten subjects. Before and after the
injections, heat testing was performed with a non-contact
laser thermal stimulator. Heat pain threshold was measured by means of a 'Marstock' technique in which subjects pressed a reaction time key when they perceived that a slowly increasing heat stimulus (1 degrees C/s ramp from a 36 degrees C base) was painful. In addition, the subjects used magnitude estimation techniques to rate the intensity of
pain to a suprathreshold heat stimulus (47 degrees C, 2 s). Mechanical testing was done using 200-microm diameter probes attached to calibrated weights that provided forces over the range of 16-512 mN. The
intradermal injections of
norepinephrine,
phenylephrine and
brimonidine produced little evoked
pain. However, a dose-dependant decrease in heat pain threshold, but not mechanical pain threshold, was observed. At the highest
drug dose injected, all three
adrenergic compounds produced a significant decrease in heat pain threshold compared to the saline injection. A significant increase in response to the suprathreshold heat stimulus was also found. One possible explanation for this apparent heat
hyperalgesia is that the decrease in perfusion due to the localized vasoconstriction may alter the heat response. However, in control studies we found that the non-
adrenergic vasoconstrictors,
angiotensin II and
vasopressin did not produce heat
hyperalgesia at doses that produced comparable decreases in blood flow. In addition, occlusion of blood flow with a blood pressure cuff did not lead to heat
hyperalgesia. Thus, the heat
hyperalgesia observed with the
adrenergic agonists is not due to a decrease in perfusion associated with the injection. These results indicate that alpha(1)- and alpha(2)-adrenoceptor-mediated mechanisms may play a role in sensitization of nociceptors to heat stimuli in normal skin.