Endocannabinoid system and pain: an introduction

Abstract

The endocannabinoid (EC) system consists of two main receptors: cannabinoid type 1 receptor cannabinoid receptors are found in both the central nervous system (CNS) and periphery, whereas the cannabinoid type 2 receptor cannabinoid receptor is found principally in the immune system and to a lesser extent in the CNS. The EC family consists of two classes of well characterised ligands; the N-acyl ethanolamines, such as N-arachidonoyl ethanolamide or anandamide (AEA), and the monoacylglycerols, such as 2-arachidonoyl glycerol. The various synthetic and catabolic pathways for these enzymes have been (with the exception of AEA synthesis) elucidated. To date, much work has examined the role of EC in nociceptive processing and the potential of targeting the EC system to produce analgesia. Cannabinoid receptors and ligands are found at almost every level of the pain pathway from peripheral sites, such as peripheral nerves and immune cells, to central integration sites such as the spinal cord, and higher brain regions such as the periaqueductal grey and the rostral ventrolateral medulla associated with descending control of pain. EC have been shown to induce analgesia in preclinical models of acute nociception and chronic pain states. The purpose of this review is to critically evaluate the evidence for the role of EC in the pain pathway and the therapeutic potential of EC to produce analgesia. We also review the present clinical work conducted with EC, and examine whether targeting the EC system might offer a novel target for analgesics, and also potentially disease-modifying interventions for pathophysiological pain states. Pain: Endocannabinoid: AnalgesiaFrom an evolutionary standpoint, pain can be considered a necessary evil, providing a potent warning system to protect an individual from present and future harm. However, not all pain is part of this adaptive response, e.g. persistent pain after injury healing (chronic pain) or pain arising from damage to nerve tissue (neuropathic pain). Pain is the most common complaint in those seeking a physician, and a recent study suggests that pain represents the greatest economic burden of any pathological condition in the USA, with an estimated annual cost of $565-635 billion (1) . Many chronic pain states are refractory to standard analgesics, and even in those which do respond, pain control can be incomplete or only short-term in nature. Of the imperfect currently available analgesics, the most efficacious are the opioids which exploit an endogenous pain control pathway within the central nervous system. However, opioids have significant issues with tolerance, dependence, respiratory depression and opioid-induced hyperalgesia (2) . Over the past few decades, the existence of a second endogenous anti-nociceptive pathway has been revealed: the endocannabinoid (EC) system. *Corresponding author: J. J. Burston, fax +44 (0)115 823 0142, email james.burston@nottingham.ac.uk Abbreviations: 2-AG, 2-arachidonoylglycerol; ACC, anterior cingulate cortex; AEA, anandamide; CB 1 , cannab...

Identification of the oleic acid ethanolamide (OEA) isomer cis-vaccenic acid ethanolamide (VEA) as a highly abundant 18:1 fatty acid ethanolamide in blood plasma from rats and humans

“…The endocannabinoids 2-AG and AEA as well as the endocannabinoid-like FAEAs are able to influence several physiological systems such as the networks involved in regulating pain [9], REM sleep [10] and, notably, food intake and energy balance [11]. Among these FAEAs, especially OEA gained importance because of its role in regulating food intake pathways.…”

“…Endocannabinoids and related compounds play decisive roles in different physiological pathways like the control of pain [9] or REM sleep [10]. Furthermore, food intake and energy balance are regulated by the endocannabinoid system [11], e.g., via enhanced olfactory perception [12].…”

“…Oleic acid is a common constituent of several fats and oils like olive oil, peanut oil, rapeseed oil, lard, or sunflower oil [15]. Additionally, oleic acid is the main fatty acid in mutton, veal, beef, or pork [9,15]. The presence in many frequently ingested foods makes it highly available for the endogenous synthesis of the respective FAEA.…”

Therapeutic potential of cannabis-related drugs

“…Indeed, one of the most common topics for cannabinoid action in preclinical disease models is pain. An alleviation of pain behaviours has been observed in both acute and chronic models; for review, see (Burston and Woodhams 2014;Rea et al 2007;Sagar et al 2012). Whilst the majority of studies implicate the CB 1 receptor heavily in the analgesic effects of cannabinoids, there is also good evidence that CB 2 cannabinoid receptors can contribute to these effects; for review, see (Atwood and Mackie 2010;Guindon and Hohmann 2008).…”

Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease

“…Moreover, endocannabinoids modulate neuronal, glial, and endothelial cell function, and can exert neuromodulatory, anti-excitotoxic, anti-inflammatory, and vasodilatory effects within the central and peripheral nervous systems [77]. Studies have looked at the role of endocannabinoids in stimulating appetite [78], modulating bone metabolism [79], and relieving pain [80]. As pain is a common underlying cause of NPS, particularly agitation and aggression [81], its treatment may also aid in the treatment of these co-morbid symptoms in AD.…”