N-palmitoylethanolamide synergizes the antinociception of morphine and gabapentin in the formalin test in mice

Objective The antinociceptive pharmacological interaction between N-palmitoylethanolamide (PEA) and morphine (MOR), as well as gabapentin (GBP), was investigated to obtain synergistic antinociception at doses where side effects were minimal. In addition, the possible antinociceptive mechanism of PEA + MOR or PEA + GBP combinations was explored. Methods Individual dose-response curves (DRCs) of PEA, MOR and GBP were evaluated in female mice in which intraplantar nociception was induced with 2% formalin. Isobolographic method was used to detect the pharmacological interaction in the combination of PEA + MOR or PEA + GBP. Key findings The ED50 was calculated from the DRC; the order of potency was MOR > PEA > GBP. The isobolographic analysis was obtained at a 1:1 ratio to determine the pharmacological interaction. The experimental values of flinching (PEA + MOR, Z(exp) = 2.72 +/- 0.2 mu g/paw and PEA + GBP Z(exp) = 2.77 +/- 0.19 mu g/paw) were significantly lower than those calculated theoretically (PEA + MOR Z(add) = 7.78 +/- 1.07 and PEA + GBP Z(add) = 24.05 +/- 1.91 mu g/paw), resulting in synergistic antinociception. Pretreatment with GW6471 and naloxone demonstrated that peroxisome proliferator-activated receptor alpha (PPAR alpha) and opioid receptors are involved in both interactions. Conclusions These results suggest that MOR and GBP synergistically enhance PEA-induced antinociception through PPAR alpha and opioid receptor mechanisms. Furthermore, the results suggest that combinations containing PEA with MOR or GBP could be of interest in aiding the treatment of inflammatory pain.