anandamide and Chronic-Pain

Chronic pain is a persistent, complex condition that contributes to impaired mood, anxiety and emotional problems. Osteoarthritis (OA) is one of the major causes of chronic pain in adults and elderly people. A substantial body of evidence demonstrate that hippocampal neural circuits, especially monoamine dopamine and serotonin levels, contributes to negative affect and avoidance motivation experienced during pain. Current pharmacological strategies for OA patients are unsatisfying and the endocannabinoid system modulation might represent an alternative for the treatment of OA-related pain. In the present study, we used a rat model of osteoarthritis induced by intra-articular injection of sodium monoiodoacetate to assess, 28 days post-induction, the contribution of endocannabinoid system on the possible alteration in pain perception and affective behavior, in LTP and monoamine levels in the lateral entorhinal cortex-dentate gyrus pathway. The results show that OA-related chronic pain induces working memory impairment and depressive-like behavior appearance, diminishes LTP, decreases dopamine levels and increases serotonin levels in the rat dentate gyrus. URB597 administration (i.p., 1 mg/kg) reduces hyperalgesia and mechanical allodynia, improves recognition memory and depressive-live behavior, restores LTP and normalizes monoamine levels in the hippocampus. The effect was observed 60-120 min post-treatment and was blocked by AM251, which proves the action of URB597 via the CB

Topics: Amines; Animals; Chronic Pain; Dopamine; Endocannabinoids; Hippocampus; Hyperalgesia; Osteoarthritis; Rats; Serotonin

Recent years have yielded significant advances in our understanding of microglia, the immune cells of the central nervous system (CNS). Microglia are key players in CNS development, immune surveillance, and the maintenance of proper neuronal function throughout life. In the healthy brain, homeostatic microglia have a unique molecular signature. In neurological diseases, microglia become activated and adopt distinct transcriptomic signatures, including disease-associated microglia (DAM) implicated in neurodegenerative disorders. Homeostatic microglia synthesise the endogenous cannabinoids 2-arachidonoylglycerol and anandamide and express the cannabinoid receptors CB1 and CB2 at constitutively low levels. Upon activation, microglia significantly increase their synthesis of endocannabinoids and upregulate their expression of CB2 receptors, which promote a protective microglial phenotype by enhancing their production of neuroprotective factors and reducing their production of pro-inflammatory factors. Here, we summarise the effects of the microglial cannabinoid system in the CNS demyelinating disease multiple sclerosis, the neurodegenerative diseases Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, chronic inflammatory and neuropathic pain, and psychiatric disorders including depression, anxiety and schizophrenia. We discuss the therapeutic potential of cannabinoids in regulating microglial activity and highlight the need to further investigate their specific microglia-dependent immunomodulatory effects.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Anxiety Disorders; Arachidonic Acids; Chronic Pain; Depressive Disorder; Endocannabinoids; Glycerides; Humans; Mental Disorders; Microglia; Multiple Sclerosis; Neuralgia; Neurodegenerative Diseases; Parkinson Disease; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Schizophrenia

The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

Topics: Analgesics; Animals; Arachidonic Acids; Arthritis; Cannabinoid Receptor Agonists; Chronic Pain; Disease Models, Animal; Endocannabinoids; Glycerides; Humans; Neoplasms; Neuralgia; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

The involvement of transient receptor vanilloid type-1 (TRPV1) channels in pain modulation by the brain remains understudied. The rostroventromedial medulla (RVM) plays a key role in conveying to the spinal cord pain modulatory influences triggered in higher brain centres, with co-existence of inhibitory (antinociceptive) and facilitatory (pronociceptive) effects. In spite of some reports of TRPV1 expression in the RVM, it remains unknown if endovanilloid signalling plays a direct role in local pain modulation. Here we used a model of diabetic neuropathy, the streptozotocin (STZ)-diabetic rat, to study the role of endovanilloid signalling in RVM-mediated pain modulation during chronic pain. Four weeks after diabetes induction, the levels of TRPV1 mRNA and fatty acid amide hydrolase (FAAH), a crucial enzyme for endovanilloid catabolism, in the RVM of STZ-diabetic rats were higher than control. The RVM of STZ-diabetic rats presented decreased levels of several TRPV1 endogenous ligands, namely anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Administration of capsaicin (a TRPV1 agonist) into the RVM decreased nociceptive behavioural responses in the inflammatory phase of the formalin test (phase 2). These findings suggest that diabetic neuropathy induces plastic changes of RVM endovanilloid signalling, indicating that TRPV1 may be a putative target for pain modulation in this chronic pain condition.

Topics: Amides; Amidohydrolases; Analgesics, Non-Narcotic; Animals; Arachidonic Acids; Capsaicin; Chronic Pain; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Endocannabinoids; Ethanolamines; Formaldehyde; Male; Medulla Oblongata; Nociceptive Pain; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Rats, Wistar; RNA, Messenger; TRPV Cation Channels