β-Endorphin, dynorphin A and Met-enkephalin activate one-third of cutaneous C-fiber polymodal receptors in the rat hairy skin

Alternative non-histaminergic mechanisms of pruritus involve interleukins and opioid peptides. Opioid peptides are released from dermal immunocytes upon interleukin activation. Although opioid receptor antagonists have been found to reduce intractable pruritus resistant to antihistamines, it is not clear whether opioid peptides can selectively activate nociceptive nerve endings to produce pruritus, in addition to their degranulator effects on mast cells and their desensitizing effects to noxious mechanical and thermal stimuli on nociceptors. Therefore, the present study was aimed at determining activating effects of opioid peptides, including β-endorphin, dynorphin A and Met-enkephalin, on physiologically identified cutaneous receptors. One-third of C-fiber polymodal receptors were activated by these opioid peptides and responses were characterized by a potent tachyphylaxis. Concentration thresholds ranged from 0.1 to 1 μM and latencies from 11 to 25 s (16±8 s). Response magnitudes varied considerably from one unit to another and generally did not increase at concentration above 10 μM. These units were also activated and/or sensitized by subsequent intradermal injection of bradykinin, which counteracted the opioid peptides-induced desensitization to mechanical and thermal stimuli. In conclusion, endogenous opioid peptides are pruritogenic inflammatory mediators, when activating one-third of cutaneous C-fiber polymodal receptors that are not chemically desensitized by them.