Protecting entodogenous enkephalins from their degradation using dual enkephalinase inhibitors (DENKIs) has been shown to elicit antinociceptive responses in various rodent pain models. Antinociceptive effects of the new DENKI PL265 were evaluated in mice inoculated with B16-F10 melanoma cells into the tibia. The oral administration of PL265 (12.5-100 mg/kg) reduced thermal hyperalgesia and mechanical allodynia. The antihyperalgesic effects were antagonized by earlier administration of naloxone-methiodide or cyprodime but not by naltrintodole or nor-binaltorphimine, confirming that only peripheral mu-opioid receptors were involved. Several antinociceptive drugs, acting through different pathways, like gabapentin, a ligand of calcium channel sub-unit 2, a P2X3 receptor antagonist (A-317491), a CB1 receptor agonist (ACEA), two CB2 receptor agonists (AM1241 and JWH-133), an inhibitor of the degradation of entodogenous cannabinoids (URB937) and a Nav1.7 blocker (NAV26), showed antihyperalgesic effects in this model. Isobolographic analysis of the effects of their combined administration with PL265 shows a synergy, with an interaction index from 0.3 to 0.7, except for JWH133, a drug with antihyperalgesic effects unrelated to the stimulation of opioid receptors. The synergistic antihyperalgesic effects of these drug combinations may be of clinical interest, reducing required todoses and thereby the side-effects of often ill-tolerated drugs.
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