Endocannabinoids control spasticity in a multiple sclerosis model

Abstract

Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non-spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re-uptake and hydrolysis-probably through the enhancement of endogenous levels of AEA, and, possibly, 2-arachidonoyl glycerol-significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity.

Regional distribution and effects of postmortal delay on endocannabinoid content of the human brain

“…Endocannabinoids, a novel class of lipid mediators, have been implicated in a growing number of neurological and psychiatric disorders, including schizophrenia, anxiety disorder, depression, Parkinson's disease, Alzheimer's disease, Huntington chorea and epilepsy, and have also been shown to have important neuroprotective effects in stroke and traumatic brain injury (reviewed in Pacher et al, 2006). Numerous studies have documented changes in the brain level of endocannabinoids in animal models for some of these diseases, such as Parkinson's (Di Marzo et al, 2000;Maccarrone et al, 2003), multiple sclerosis (Baker et al, 2001;Cabranes et al, 2005) or Huntington chorea (Bisogno et al, 2007), and in human brain tumors (Maccarrone et al, 2001). A tacit assumption in such studies is that the biochemical composition of the postmortem brain reliably reflects in vivo conditions.…”

Cannabinoids and neuroinflammation

“…Baker et al (2001) found that brains and spinal cords of spastic animals contained elevated levels of anandamide and 2-AG compared with control animals. Interestingly, exogenous administration of anandamide and 2-AG ameliorated spasticity within minutes (Baker et al, 2001). These results show that inflamed CNS tissues produce endocannabinoids and that augmenting this production may have a beneficial effect.…”

“…Degradation Baker et al (2001) also used mice with EAE to examine the potential for pharmacologically targeting the FAAH enzyme as a treatment of neuroinflammation. A pharmacological inhibitor of FAAH, as well as inhibitors of the putative anandamide transporter, reduced spasticity within minutes, and effects were blocked by the administration of SR141716A in conjunction with SR144528 (Baker et al, 2001).…”

“…A pharmacological inhibitor of FAAH, as well as inhibitors of the putative anandamide transporter, reduced spasticity within minutes, and effects were blocked by the administration of SR141716A in conjunction with SR144528 (Baker et al, 2001). The specific cells involved in neuoinflammation that are capable of degrading endocannabinoids are discussed below.…”

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

“…Thus, the effects observed here upon um-PEA administration can be due to PEA activating its molecular targets, and also to PEA favoring the actions of other NAEs (e.g., AEA and OEA). Indeed, anti-inflammatory, neuroprotective, and analgesic effects have been reported for AEA and OEA in several preclinical models [69][70][71][72][73].…”