Endocannabinoids analgesic effect: science explained

With the groundbreaking identification of the Cannabinoid Receptors (CB1 in 1990 and CB2 in 1993), it seemed somehow evident that our body must produce its natural ligands (the substances that bind and activate receptors). (1,2)

N-arachidonoyl ethanolamide was the compound firstly isolated that could strongly activate CB1 receptor. We currently call this compound AEA or Anandamide, from the Sanskrit word
for “eternal bliss”.

Only a few years later a brother compound has been characterised, and was found to successfully activate both cannabinoid receptors, CB1 and CB2. This was named 2-arachidonylglycerol (2-AG).

Cannabinoid receptor distribution

2-AG and AEA are, respectively, an ester and an amide of the family of polyunsaturated fatty acid; they are similar in structure to the notorious Δ9-thetrahydrocannabinol (D9THC), as they activate non-specifically both CB1, CB2 and the novel putative cannabinoid receptor GPR55, but differ from it as they are “endogenous” of our bodies, therefore endocannabinoids (ECs). (5)

The prevalence of Cannabinoid Receptors both in the brain and at the periphery is incredibly dense and variegate, thus contributing to the large therapeutic profile of cannabinoids medicinals. (3)

The CB1 receptor is expressed in neuronal tissue, both centrally and peripherally, as well as in other peripheral organs. CB1 receptors are present at lower densities in the heart, lung, testis, ovary, bone marrow, thymus, uterus and immune cells. (6)

CB2 receptors are mainly expressed at high densities in immune tissues, including macrophages, mast cells, and the spleen. Their presence in the central nervous system is mainly located at the spinal cord. (8)

CB1 receptors are highly located in regions involved in pain transmission and modulation, such as dorsal root ganglia (DRG), spinal cord, thalamus, periaqueductal grey (PAG), amygdala and rostroventromedial medulla. (7)

CB2 receptors are also present in the skin. Their activation is reported to release endorphins from keratinocytes, acting via μ opioid receptors to produce analgesia. (9)

It is well established that activation of the EC system reduces pain sensation at central and peripheral levels.

Numerous evidences show that AEA and 2-AG induce analgesia. (10)

Following injury, endocannabinoids levels increase, both at the site of inflammation as well as at other targets of the descending pathway of pain.

This reaction is the body’s first analgesic response to pain: it synthesize more endocannabinoids, thus playing a double role:

1) inhibiting the conduction of nerve endings which are shooting pain sensation

2) engaging anti-inflammatory mediators thus reducing the damage at the site of injury

The cannabinoid system induces its analgesics effects via multiple mechanisms, involving other pathways too like opioids, vanilloids, prostglandins and adrenergic receptors.

Inducing their activation, either via increase release or via blockade of the enzymes that re-uptake endocannabinoids, benefits a vast range of pain-related illnesses.

Acute pain, postoperative pain, chronic pain (such as in Multiple Sclerosis), Neuropathic pain, Cancer pain, Fibromyalgia, Migraine, Spasticity, Phantom Limb Syndrome are just some of the many conditions for which cannabinoid treatment has been proven more effective than the currently available treatments, generally opioids and anti-inflammatory drugs.

Basic research on how cannabinoid receptors and endocannabinoids intervene in pain mechanisms is progressing rapidly. Clinical progress, however, is advancing slowly. One of the drawbacks of investigating cannabinoids is their typification as substances of abuse.

Our current understanding of the physiology and pharmacology of the endogenous cannabinoid system has motivated cannabis-based therapeutic drug design, in which attempts are being made to synthesise compounds with the desired therapeutic actions but without psychoactive adverse effects.

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8) Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, Reggiani A: CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci 2006, 23:1530-1538.

9) Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata HP, Malan TP Jr: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 2005, 102:3093-3098

10) Pertwee RG: Cannabinoid receptors and pain. Prog Neurobiol 2001, 63:569-611