ABSTRACT
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. In naïve rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears to be an innovative approach to treat migraine.
Subject(s)
Migraine Disorders , Neprilysin , Animals , Enkephalins , Hyperalgesia , Isosorbide Dinitrate , Male , RatsABSTRACT
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. The aim of this study was to explore the antinociceptive and anti-inflammatory effects of topical administration of PL265 (a dual enkephalinase inhibitor) on murine models of corneal pain. On healthy corneas, chronic PL265 topical administration did not alter corneal integrity nor modify corneal mechanical and chemical sensitivity. Then, on murine models of corneal pain, we showed that repeated instillations of PL265 (10 mM) significantly reduced corneal mechanical and chemical hypersensitivity. PL265-induced corneal analgesia was completely antagonized by naloxone methiodide, demonstrating that PL265 antinociceptive effects were mediated by peripheral corneal opioid receptors. Moreover, flow cytometry (quantification of CD11b+ cells) and in vivo confocal microscopy analysis revealed that instillations of PL265 significantly decreased corneal inflammation in a corneal inflammatory pain model. Chronic PL265 topical administration also decreased Iba1 and neuronal injury marker (ATF3) staining in the nucleus of primary sensory neurons of ipsilateral trigeminal ganglion. These results open a new avenue for ocular pain treatment based on the enhancement of endogenous opioid peptides' analgesic effects in tissues of the anterior segment of the eye. Dual enkephalinase inhibitor PL265 seems to be a promising topical treatment for safe and effective alleviation of ocular pain and inflammation.
Subject(s)
Cornea/pathology , Enzyme Inhibitors/administration & dosage , Inflammation/drug therapy , Pain/drug therapy , Propionates/administration & dosage , Administration, Topical , Animals , Anti-Infective Agents, Local/therapeutic use , Benzalkonium Compounds/therapeutic use , Capsaicin/toxicity , Cornea/drug effects , Corneal Injuries/chemically induced , Corneal Injuries/complications , Disease Models, Animal , Hyperalgesia/physiopathology , Inflammation/chemically induced , Lipopolysaccharides/toxicity , Male , Mice , Mice, Inbred C57BL , Naloxone/toxicity , Narcotic Antagonists/toxicity , Pain/etiology , Pain Threshold/drug effects , Sensory System Agents/toxicity , Trigeminal Ganglion/metabolism , Trigeminal Ganglion/pathologySubject(s)
Analgesics/pharmacology , Opioid Peptides/metabolism , Proteolysis/drug effects , Analgesia/methods , Analgesia/trends , Analgesics/adverse effects , Analgesics/therapeutic use , Animals , Disulfides/adverse effects , Disulfides/pharmacology , Disulfides/therapeutic use , Down-Regulation/drug effects , Drug Design , Drugs, Investigational/adverse effects , Drugs, Investigational/pharmacology , Drugs, Investigational/therapeutic use , Humans , Models, Biological , Propylamines/adverse effects , Propylamines/pharmacology , Propylamines/therapeutic use , Protein Processing, Post-Translational/drug effectsABSTRACT
Chronic pain remains unsatisfactorily treated, and few novel painkillers have reached the market in the past century. Increasing the levels of the main endogenous opioid peptides - enkephalins - by inhibiting their two inactivating ectopeptidases, neprilysin and aminopeptidase N, has analgesic effects in various models of inflammatory and neuropathic pain. Stemming from the same pharmacological concept, fatty acid amide hydrolase (FAAH) inhibitors have also been found to have analgesic effects in pain models by preventing the breakdown of endogenous cannabinoids. Dual enkephalinase inhibitors and FAAH inhibitors are now in early-stage clinical trials. In this Review, we compare the effects of these two potential classes of novel analgesics and describe the progress in their rational design. We also consider the challenges in their clinical development and opportunities for combination therapies.
