Modulation of peripheral inflammation by locally administered hemorphin-7

Objective: Sensory nerves mediate peripheral inflammation via the release of sensory peptides at the site of tissue injury. Using a blister model of inflammation, we have previously documented that endogenous opioids modulate chronic but not acute inflammation. Hemorphins are nonclassical opioid peptides found in the region of the beta-chain of hemoglobin (Hb). The heptapeptide hemorphin-7 is identical with residues 35-41 of the beta-chain of the human Hb. The aim of this study was to examine the effect of hemorphin-7 on the inflammatory response in acute and chronic injury models. Methods: We have used a vacuum-induced blister model in the footpad of anaesthetized rats to induce an inflammatory response in naive skin by (a) electrical stimulation (ES) of the distal end of the cut sciatic nerve at 20 V, 5 Hz, 2 ms for 1 min or (b) superfusion of sensory peptides; substance P (SP) or calcitonin gene related peptide (CGRP) over the blister base. In addition, we examined the effect of hemorphin-7 on the inflammatory response to SP induced in a previously injured but healed skin site (recurrent injury model) and in denervated skin site due to chronic nerve lesion (chronic injury model). Results: The results showed that prior and concomitant perfusion of hemorphin-7 over the blister base inhibited the acute inflammatory response to ES of the sciatic nerve at C-fibre strength in a dose-dependent manner. Significant inhibition was achieved at 20 and 200 mu M concentration of hemorphin-7. When hemorphin-7 (20 mu M) was perfused prior to and together with SP or CGRP (both at 1 mu M), over the base of acutely induced blister in naive skin, it significantly reduced the inflammatory response to SP (both plasma extravasation and vasodilatation), but was without effect on the vasodilatation response to CGRP. Naloxone, the general opioid antagonist at (1 mg/kg i.v.) reversed the inhibitory effect of hemorphin-7 on the inflammatory response to SP. On the other hand, hemorphin-7 had no effect on the inflammatory response to SP in the recurrent injury or the chronic injury models. Conclusions: The results of this study suggest that hemorphins might play a role in inhibiting the inflammatory response in acute, but not in recurrent or chronic injury conditions. Evidence is also provided that the modulatory inhibitory effect of hemorphin-7 is mediated via activation of opioid receptor(s). The significance of this study in conjunction with our previous work, is that it raises the possibility that different endogenous inhibitory mechanisms may operate under different injury conditions - endogenous hemorphins and opioids may modulate acute and chronic inflammation, respectively.