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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, Zexp = 2.72 ± 0.2 μg/paw and PEA + GBP Zexp = 2.77 ± 0.19 μg/paw) were significantly lower than those calculated theoretically (PEA + MOR Zadd = 7.78 ± 1.07 and PEA + GBP Zadd = 24.05 ± 1.91 μg/paw), resulting in synergistic antinociception. Pretreatment with GW6471 and naloxone demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) and opioid receptors are involved in both interactions.

Conclusions: These results suggest that MOR and GBP synergistically enhance PEA-induced antinociception through PPARα 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.

Comments：

The objective of this study was to investigate the antinociceptive pharmacological interaction between N-palmitoylethanolamide (PEA) and morphine (MOR) or gabapentin (GBP) in female mice with intraplantar nociception induced with 2% formalin, in order to achieve synergistic antinociception at doses with minimal side effects. The study also aimed to explore the possible antinociceptive mechanism of these combinations.

The study used individual dose-response curves (DRCs) to evaluate the potency of PEA, MOR, and GBP. The order of potency was found to be MOR > PEA > GBP. The isobolographic method was then used to detect the pharmacological interaction in the combination of PEA + MOR or PEA + GBP, with the experimental values of flinching significantly lower than those calculated theoretically. This indicates synergistic antinociception.

The study further demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) and opioid receptors are involved in both interactions, as pretreatment with GW6471 and naloxone blocked the effects. Therefore, the results suggest that combinations containing PEA with MOR or GBP could be useful in treating inflammatory pain.

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S2798 GW6471 GW 6471 is a potent antagonist of PPARα with IC50 of 0.24 μM.

Related Targets

PPAR