Melatonin synergizes with the antinociceptive effect of N-palmitoylethanolamide and paracetamol.

Melatonin has been shown to have an antinociceptive effect and its administration could enhance the antinociceptive effect of other drugs. This study assessed the antinociceptive effects of melatonin in combination with paracetamol and N-palmitoylethanolamide (PEA) using the formalin test in mice. Melatonin, paracetamol, and PEA were administered intraplantarly (paw) alone or combined to mice. A concentration-response curve was generated to determine the concentration needed to reach 30% of the maximal antinociceptive effect (EC30). Melatonin, paracetamol and PEA induced a concentration-dependent antinociceptive effect in both phases of the formalin test, being PEA more potent (EC30 = 7.4±0.2 mg/paw) than melatonin (EC30 = 20.5±3.1 mg/paw) or paracetamol (EC30 = 41.8±2.6 mg/paw). Combinations of melatonin with paracetamol or PEA also induced a concentration-dependent antinociceptive effect in the formalin test. Isobolographic analysis showed that melatonin interacts synergistically with either paracetamol or PEA to reduce formalin-induced inflammatory pain. However, the experimental values of EC30 were significantly smaller than those calculated theoretically.

A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability.

It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the tryptophan REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides, to multitryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibodies in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating biomolecular simulation with experimental data to yield novel insights.