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

Objective: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect.

Background: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co-administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects.

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

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.

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model.

The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioural testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate.

Dual enkephalinase inhibitor PL265: a novel topical treatment to alleviate corneal pain and inflammation.

Ocular pain is a core symptom of inflammatory or traumatic disorders affecting the anterior segment. To date, the management of chronic ocular pain remains a therapeutic challenge in ophthalmology. The main endogenous opioids (enkephalins) play a key role in pain control but exhibit only transient analgesic effects due to their rapid degradation.

Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain.

Background: The first line pharmacological treatment of cancer pain is morphine and surrogates but a significant pain relief and a reduction of the side-effects of these compounds makes it necessary to combine them with other drugs acting on different targets. The aim of this study was to measure the antinociceptive effect on cancer-induced bone pain resulting from the association of the endogenous opioids enkephalin and non-opioid analgesic drugs. For this purpose, PL265 a new orally active single dual inhibitor of the two degrading enkephalins enzymes, neprilysin (NEP) and aminopeptidase N (APN) was used.