Endocannabinoids And PUFA

[Jack Roe]

It seems that the endogenous CB1/CB2 ligands are all PUFA derivatives, tho I may be wrong. I understand that it is impossible to avoid PUFA, so there are three possibilites:

(1) There is no need for endogenous CB1/CB2 ligands
(2) Very small amounts of PUFA are sufficient and will be present in all diets, except the "impossible" PUFA-free diet
(3) There are undiscovered non-PUFA-derived ligands.

But would this not contradict Peat's view that these substances are toxic and unnecessary in any quantity? The requirement may be very low, but is there not some need to produce the endogenous cannbinoids? I can't find anything from Peat himself, but everything I have read indicates that all of the ligands derive from omega6 -> arachidonic acid. In fact, if (2) is correct, would it not make omega6 essential, if CB1/CB2 ligands are essential for health/wellness? If not, why is the CB1/CB2 receptor spread throughout the body? Is it a way of binding these toxic substances for some purpose, until they can be disposed of?

 

[Jack Roe]

Update:

It seems that oleamide is a full CB1 agonist, not necessarily much activity at CB2.

(no links because I am not allowed to post links!)


"Biosynthesis of oleamide.
Mueller GP1, Driscoll WJ.
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Abstract
Oleamide (cis-9-octadecenamide) is the prototype long chain primary fatty acid amide lipid messenger. The natural occurrence of oleamide was first reported in human serum in 1989. Subsequently oleamide was shown to accumulate in the cerebrospinal fluid of sleep-deprived cats and to induce sleep when administered to experimental animals. Accordingly, oleamide first became known for its potential role in the mechanisms that mediate the drive to sleep. Oleamide also has profound effects on thermoregulation and acts as an analgesic in several models of experimental pain. Although these important pharmacologic effects are well establish, the biochemical mechanism for the synthesis of oleamide has not yet been defined. This chapter reviews the biosynthetic pathways that have been proposed and highlights two mechanisms which are most supported by experimental evidence: the generation of oleamide from oleoylglycine by the neuropeptide processing enzyme, peptidylglycine alpha-amidating monooxygenase (PAM), and alternatively, the direct amidation of oleic acid via oleoyl coenzyme A by cytochrome c using ammonia as the nitrogen source. The latter mechanism is discussed in the context of apoptosis where oleamide may play a role in regulating gap junction communication. Lastly, several considerations and caveats pertinent to the future study oleamide biosynthesis are discussed."


"Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors
James D Leggett,1,* S Aspley,2,4 S R G Beckett,1 A M D'Antona,3 D A Kendall,3 and D A Kendall1
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Abstract

1. The ability of the endogenous fatty acid amide, cis-oleamide (ODA), to bind to and activate cannabinoid CB1 and CB2 receptors was investigated.
2. ODA competitively inhibited binding of the nonselective cannabinoid agonist [3H]CP55,940 and the selective CB1 antagonist [3H]SR141716A to rat whole-brain membranes with Ki values of 1.14 μM (0.52–2.53 μM, Hill slope=0.80, n=6) and 2.63 μM (0.62–11.20 μM, Hill slope=0.92, n=4), respectively. AEA inhibited [3H]CP55,940 binding in rat whole-brain membranes with a Ki of 428 nM (346–510 nM, Hill slope=−1.33, n=3).
3. ODA competitively inhibited [3H]CP55,940 binding in human CB1 (hCB1) cell membranes with a Ki value of 8.13 μM (4.97–13.32 μM, n=2). In human CB2 transfected (hCB2) HEK-293T cell membranes, 100 μM ODA produced only a partial (42.5±7%) inhibition of [3H]CP55,940 binding.
4. ODA stimulated [35S]GTPγS binding in a concentration-dependent manner (EC50=1.64 μM (0.29–9.32 μM), R2=0.99, n=4–9), with maximal stimulation of 188±9% of basal at 100 μM. AEA stimulated [35S]GTPγS binding with an EC50 of 10.43 μM (4.45–24.42 μM, R2=1.00, n=3, 195±4% of basal at 300 μM). Trans-oleamide (trans-ODA) failed to significantly stimulate [35S]GTPγS binding at concentrations up to 100 μM.
5. ODA (10 μM)-stimulated [35S]GTPγS binding was reversed by the selective CB1 antagonist SR141716A (IC50=2.11 nM (0.32–13.77 nM), R2=1.00, n=6).
6. The anatomical distribution of ODA-stimulated [35S]GTPγS binding in rat brain sections was indistinguishable from that of HU210. Increases of similar magnitude were observed due to both agonists in the striatum, cortex, hippocampus and cerebellum.
7. ODA (10 μM) significantly inhibited forskolin-stimulated cyclic AMP (cAMP) accumulation in mouse neuroblastoma N1E 115 cells (P=0.02, n=11). ODA-mediated inhibition was completely reversed by 1 μM SR141716A (P<0.001, n=11) and was also reversed by pretreatment with 300 ng ml−1 pertussis toxin (P<0.001, n=6).
8. These data demonstrate that ODA is a full cannabinoid CB1 receptor agonist. Therefore, in addition to allosteric modulation of other receptors and possible entourage effects due to fatty acid amide hydrolase inhibition, the effects of ODA may be mediated directly via the CB1 receptor.

Keywords: Cis-9,10-octadecanoamide, oleamide (ODA); HU210; 11-hydroxy-dimethylheptyl-Δ8-tetrahydrocannabinol; cannabinoid agonist; endocannabinoid; CB1 receptor; CB2 receptor; rat; human; radioligand binding; [35S]GTPγS binding"