Efficacy of dual enkephalinase inhibition in a preclinical migraine model is mediated by activation of peripheral delta opioid receptors

Abstract

Objective The aim of this study was to evaluate whether elevating levels of enkephalin by inhibiting their degradation can attenuate stress‐induced migraine‐like behaviors in mice. Background Previous studies in animals have suggested the delta opioid receptor (DOR) as a novel migraine target. The primary endogenous ligands for DOR are enkephalins and their levels can be increased by pharmacological inhibition of enkephalinases; however, it is not clear whether enkephalinase inhibition can be efficacious in preclinical migraine models through activation of DOR or whether other opioid receptors might be involved. Further, it is not clear whether opioid receptors in the central nervous system are necessary for these effects. Methods This study used a model of repetitive restraint stress in mice that induces periorbital hypersensitivity and priming to the nitric oxide donor sodium nitroprusside (SNP; 0.1 mg/kg). Von Frey filaments were used to measure periorbital mechanical thresholds and grimace scores were evaluated by observing mouse facial features. Animals were treated with the dual enkephalinase inhibitor (DENKI) PL37. Results On day two post‐stress, PL37 given to mice via either intravenous injection (10 mg/kg) or oral gavage (20 mg/kg) significantly attenuated stress‐induced periorbital hypersensitivity and facial grimace responses. Additionally, both intravenous (10 mg/kg) and oral gavage (20 mg/kg) of PL37 prior to SNP (0.1 mg/kg) administration on day 14 post‐stress significantly reduced SNP‐induced facial hypersensitivity. Injection of the DOR antagonist naltrindole (0.1 mg/kg) but not the mu‐opioid receptor antagonist CTAP (1 mg/kg) prior to PL37 treatment blocked the effects. Finally, pretreatment of mice with the peripherally restricted opioid receptor antagonist naloxone methiodide (5 mg/kg) blocked the effects of PL37. Conclusions These data demonstrate that inhibiting enkephalinases, and thus protecting enkephalins from degradation, attenuates stress‐induced migraine‐like behavior via activation of peripheral DOR. Peripheral targeting of endogenous opioid signaling may be an effective therapeutic strategy for migraine.

Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine

“…Indeed, previous studies using other pain models have reported that pretreatment with the peripherally acting opioid receptor antagonist naloxone methiodide reduced, albeit partially, the antinociceptive effect of PL37 36 . Furthermore, a recent study revealed that the analgesic effects of PL37 were mainly mediated by DOR activated in the peripheral nervous system 11 . This is consistent with previous findings showing that DOR may be a potential target for migraine therapy 37 .…”

“…The analgesic effect of PL37 has been demonstrated in various preclinical rodent models of pain, as oral administration of PL37 produced antinociception in the hot plate test 24 and in a murine model of bone cancer pain 25,26 . More recently, PL37 was found to be effective in two preclinical models of migraine 10,11 . Accordingly, we showed that oral administration of PL37 dose‐dependently inhibited ISDN‐induced cephalic MH in rats.…”

“…Recently, the efficacy of PL37 was demonstrated in two preclinical migraine models. PL37 treatment effectively inhibited isosorbide dinitrate–induced cephalic mechanical hypersensitivity (MH) in rats 10 and attenuated stress‐induced cephalic MH and facial grimace responses in mice 11 . These findings support the approach of inhibiting enkephalinases as a novel migraine therapeutic strategy.…”

“…Although the model used herein has only been validated in males and requires further validation using female animals for the migraine‐alleviating effect of PL37 to be extended to females in a dedicated study, sumatriptan, which decreases MH in the herein model, has also been shown to decrease MH in a similar model of migraine, using nitroglycerin, in both male and female animals. Moreover, PL37 was also recently shown to decrease stress‐induced MH using both male and female mice 11 . As the endogenous opiate system is highly conserved across species, one could hypothesize that female rats should respond in a manner similar to that observed in males.…”

“…The vehicle group received per os a solution containing 80% of 0.9% NaCl and 20% of anhydrous ethanol. The drugs were dissolved in the corresponding vehicle with no pH adjustment and free base versus salt ratio was not taken into account during drug preparation, as described in previous studies 10,11,25,26 . Doses correspond to the drugs as salts.…”