PEA has been proven by many studies to be a natural anti-inflammatory compound and a natural painkiller. Here we present some interesting findings from 2005, when the scientific community was still unaware of the exact mechanism of action of PEA. However, interesting is that PEA also in the models of respiratory inflammation was clearly protective.
In the paper ‘Endogenous Cannabinoid Receptor Agonists Inhibit Neurogenic Inflammations in Guinea Pig Airways‘ by
Shigemi Yoshiharaa and colleages the authors examined the effects palmitoylethanolamide, on the activation of C fibers in guinea pig airway tissues.
They suggested that PEA has inhibitory effects on airway inflammation induced by the activation of C fibers via the opening of maxi-K+ channels. Their interpretation at that time was that this happened via the cB 2 receptors, but now we know this must have been an incorrect finding, as PEA does not have any affinity for CB 2 receptors.
Their results suggested that PEA might endogenously and negatively regulate the release of tachykinins from the endings of C fibers in guinea pig airways via the opening of maxi-K+ channels.
Effects of PEA on Isolated Guinea Pig Bronchial Smooth Muscle Contraction
The effects of PEA on isolated guinea pig bronchial smooth muscle contraction was examined. After electrical field stimulation in the presence of atropine and propranolol, isolated guinea pig bronchial smooth muscles evoked tachykinin-dependent prolonged contraction. Electrical field stimulation and 1 nM neurokinin A elicited the guinea pig isolated bronchial smooth muscle contraction and palmitoylethanolamide (0.0033–3.3 μM), dose-dependently inhibited electrical field stimulation-induced tachykinin-dependent contraction.
The authors also tested anadamide, but palmitoylethanolamide worked stronger.
The facts that the selective cannabinoid CB1 (SR 141716A) and CB2 (SR 144528) receptor antagonists. SR 144528 (10 nM) reduced the inhibitory effects of anandamide and palmitoylethanolamide on the guinea pig bronchial smooth muscle contraction induced by electrical field stimulation lead them to believe CB 1 and 2 were the mechanisms of action. Meanwhile we know these antagonsts are not specific enough and PEA does not have any affinity for these receptors, but works via other mechanisms (GRP55 and PPAR-alpha).
Anandamide (0.43 and 4.3 μM) and palmitoylethanolamide (0.05 and 0.5 μM) both significantly inhibited the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Palmitoylethanolamide being a lot stronger in its efficacy than anandamide.
The authors remained puzzled by the mechanism of action, as they wrote:
Although there is no doubt about the anti-inflammatory effect of these endogenous cannabinoid receptor agonists in rodents, the molecular mechanisms underlying their actions have been puzzles. In this study, we found that both anandamide and palmitoylethanolamide inhibited electrical field stimulation-induced isolated guinea pig bronchial smooth muscle contraction and capsaicin-induced guinea pig bronchoconstriction. These reactions are dependent on tachykinins because they were inhibited by tachykinin receptor antagonists
When excitatory C fibers are stimulated, not only substance P but other neuropeptides, e.g. neurokinin A and calcitonin gene-related peptide, are also released from their nerve endings and exert various respiratory reactions. The inflammatory effects of these neuropeptides on airway tissues may be of pathological relevance in human bronchial hyperreactivity, and we showed that antiasthmatic compounds, disodium cromoglycate and nedocromil sodium, inhibited hypertonic saline-induced plasma extravasation in guinea pig airways by the inactivation of C fibers. We conclude that endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, which inhibit the activation of C fibers and the release of these neuropeptides from their endings via the opening of maxi-K+ channels by the activation of CB2 receptors, might be involved in the clinical effects of antiasthmatic compounds described above.
Shigemi Yoshiharaa et al. Endogenous Cannabinoid Receptor Agonists Inhibit Neurogenic Inflammations in Guinea Pig Airways Int Arch Allergy Immunol 2005;138:80-87