N-Palmitoyl-ethanolamine (PEA) Induces Peripheral Antinociceptive Effect by ATP-Sensitive K+-Channel Activation

Synergistic antinociceptive interaction between palmitoylethanolamide and tramadol in the mouse formalin test

“…It is possible that the synergistic antinociceptive responses obtained with the combination of PEA and tramadol might potentiate their individual antinociceptive effects through a multi-target mechanism of action. PEA is known as a "promiscuous" drug for its broad spectrum of pharmacological activities including interactions with G protein-coupled receptors 55 and 119 (Ryberg et al, 2007;Overton et al, 2006), nuclear receptors PPAR-// (Fehrenbacher et al, 2009), TRPV1 (Ambrosino et al, 2013;Costa et al, 2008), adenosine triphosphate-sensitive K + channels and Ca 2+ -activated K + channels (Romero and Duarte 2012). Several studies have shown that inhibitors of fatty acid amide hydrolase, an enzyme that metabolizes endocannabinoids, reduce spinal nociceptive responses and that this effect may be linked to activation of the opioid system.…”

“…Synthesis and degradation of PEA occur in various cell types, including those relevant for chronic pain and inflammation signalling, such as immune cells, neurons and microglia (Skaper and Facci, 2012). Several reports note that PEA has antinociceptive, anti-hyperalgesic and anti-allodynic properties (Costa et al, 2008;Romero and Duarte 2012). The proposed mechanisms of action include the "entourage effect:" anandamide potentiation effect through the cannabinoid or transient receptor potential cation channel subfamily V member 1 or "TRPV1" (De Petrocellis et al, 2001;Smart et al, 2002).…”

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP-sensitive K+ channels pathway activation in mice

“…The NO/cGMP pathway and the activation of the KATP channels on the peripheral antinociception was demonstrated for several analgesics: morphine (Rodrigues and Duarte, 2000;Cunha et al, 2010), ketorolac (Lázaro-Ibáñez et al, 2001); dipyrone (Alves and Duarte, 2002); diclofenac (Ortiz et al, 2003;Alves et al, 2004), xylazine Duarte, 2009a, 2009b), for the agonist of the cannabinoid receptor CB 1 , anandamide (Reis et al, 2011), for the agonist of the cannabinoid receptor CB 2 , palmitoylethanolamide (PEA) (Romero and Duarte, 2012a), among others, and in the present study, we observed that tingenone induced a peripheral antinociceptive effect by this pathway activation, with potential to be an analgesic drug. Fig.…”

“…The L-arginine/NO/cGMP pathway and activation of KATP was described as the peripheral antinociceptive mechanism for opioid agonists (Ferreira et al, 1991;Rodrigues and Duarte, 2000;Pacheco et al, 2005), ketorolac (Lázaro-Ibáñez et al, 2001); diclofenac (Ortiz et al, 2003;Alves et al, 2004), cannabinoids (Reis et al, 2011;Romero and Duarte, 2012a), dipyrone and myrcene (terpene) (Duarte et al, 1992), melatonin (Hernández-Pacheco et al, 2008), among others. In a previous study accomplished by Veloso et al (2014b), it was demonstrated that tingenone administered into the right hind paw induced a local antinociceptive effect that was antagonized by naloxone, a non-selective antagonist to opioid receptors, suggesting that the opioidergic system participates in the peripheral antinociception induced by tingenone.…”

Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy

“…The pharmacological properties of PEA with respect to pain, inflammation and mechanism(s) of action in preclinical models have been well reviewed elsewhere and will only be mentioned briefly here. PEA shows efficacy in a variety of pain models including carrageenan‐ and prostaglandin‐induced hyperalgesia , the formalin test of persistent pain , visceral hyperalgesia produced by instillation of nerve growth factor into the bladder , and the sciatic nerve ligature model of neuropathic pain , whereas the acute thermal pain response is not affected . The proposed mechanism(s) of action of PEA involve effects upon mast cells , CB 2 ‐like cannabinoid receptors , ATP‐sensitive K + ‐channels , TRP channels , and NFkB , although the most robust evidence is for an action of PEA upon the nuclear receptor peroxisome proliferator‐activated receptor α (PPARα) .…”