The cannabinomimetic arachidonyl‐2‐chloroethylamide (ACEA) acts on capsaicin‐sensitive TRPV<sub>1</sub> receptors but not cannabinoid receptors in rat joints

Baker, Chris; McDougall, Jason J.

doi:10.1038/sj.bjp.0705902

Cited by 44 publications

(26 citation statements)

References 41 publications

(63 reference statements)

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“…An interesting aspect of the anandamide study was that its stimulatory effect on joint nociceptors was attained by activating the transient receptor potential (TRP) vanilloid channel 1 (TRPV 1 ). This pathway was reaffirmed by joint blood flow experiments that showed that the vasomotor effects of a selective CB 1 agonist in rat knees could be blocked by TRPV 1 antagonism [87]. Zygmunt and coworkers [88] deduced that anandamide activation of TRPV 1 channels on sensory nerves causes the secondary release of CGRP.…”

Section: Factors Contributing To Joint Peripheral Sensitizationmentioning

confidence: 94%

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McDougall

2006

Arthritis Res Ther

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219

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Arthritis pain affects millions of people worldwide yet we still have only a limited understanding of what makes our joints ache. This review examines the sensory innervation of diarthroidal joints and discusses the neurophysiological processes that lead to the generation of painful sensation. During inflammation, joint nerves become sensitized to mechanical stimuli through the actions of neuropeptides, eicosanoids, proteinase-activated receptors and ion channel ligands. The contribution of immunocytes to arthritis pain is also reviewed. Finally, the existence of an endogenous analgesic system in joints is considered and the reasons for its inability to control pain are postulated. IntroductionAccording to a recent report released by the World Health Organization [1], musculoskeletal disorders are the most frequent cause of disability in the modern world, and the prevalence of these diseases is rising at an alarming rate. The most prominent reason for loss of joint mobility and function is chronic or episodic pain, which leads to psychological distress and impaired quality of life. Current therapies to help alleviate joint pain have limited effectiveness and certain drugs produce unwanted negative side effects, thereby precluding their long-term use. In short, millions of patients are suffering from the debilitating effects of joint pain for which there is no satisfactory treatment. One of the reasons for this lack of effective pain management is the paucity in our knowledge of what actually causes joint pain. We are only now starting to identify some of the mediators and mechanisms that cause joints to become painful, allowing us to develop future new targets that could better alleviate arthritis pain. This review summarizes what is known about the origin of joint pain by describing the neurobiological processes initiated in the joint that give rise to neural signals and that are ultimately decoded by the central nervous system into pain perception. Joint innervation and nociceptionKnee joints are richly innervated by sensory and sympathetic nerves [2,3]. Postganglionic sympathetic fibres terminate near articular blood vessels, where they regulate joint blood flow through varying degrees of vasoconstrictor tone. The primary function of sensory nerves is to detect and transmit mechanical information from the joint to the central nervous system. Large diameter myelinated nerve fibres encode and transmit proprioceptive signals, which can be interpreted as being either dynamic (movement sensations) or static (position sense). Pain-sensing nerve fibres are typically less than 5 µm in diameter and are either unmyelinated (type IV) or myelinated with an unmyelinated 'free' nerve ending (type III). These slowly conducting fibres typically have a high threshold and only respond to noxious mechanical stimuli, and as such are referred to as nociceptors [4]. In the rat and cat, 80% of all knee joint afferent nerve fibres are nociceptive [5][6][7], suggesting that joints are astutely designed to sense abnormal and p...

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Section: Factors Contributing To Joint Peripheral Sensitizationmentioning

confidence: 94%

Untitled

McDougall

2006

Arthritis Res Ther

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219

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“…5,9,27,28 Evidence is also emerging for the existence of several other pharmacological targets that respond to at least some established cannabinoid receptor agonists or to abnormal-cannabidiol, a synthetic analogue of the plant cannabinoid cannabidiol that lacks significant affinity for both CB 1 and CB 2 receptors. 5,9 These include:…”

Section: 26mentioning

confidence: 99%

The pharmacology of cannabinoid receptors and their ligands: an overview

2006

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Mammalian tissues express at least two cannabinoid receptor types, CB 1 and CB 2 , both G protein coupled. CB 1 receptors are found predominantly at nerve terminals where they mediate inhibition of transmitter release. CB 2 receptors occur mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous agonists for cannabinoid receptors also exist, and are all eicosanoids. The first-discovered of these 'endocannabinoids' was arachidonoylethanolamide and there is convincing evidence that this ligand and some of its metabolites can activate vanilloid VRI (TRPV1) receptors. Certain cannabinoids also appear to have TRPV1-like and/or non-CB 1 , non-CB 2 , non-TRPV1 targets. Several CB 1 -and CB 2 -selective agonists and antagonists have been developed. Antagonists include the CB 1 -selective SR141716A, AM251, AM281 and LY320135, and the CB 2 -selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB 1 and CB 2 receptors can exist in a constitutively active state. 'Neutral' cannabinoid receptor antagonists have also been developed. CB 1 and/or CB 2 receptor activation appears to ameliorate inflammatory and neuropathic pain and certain multiple sclerosis symptoms. This might be exploited clinically by using CB 1 , CB 2 or CB 1 /CB 2 agonists, or inhibitors of the membrane transport or catabolism of endocannabinoids that are released in increased amounts, at least in animal models of pain and multiple sclerosis. We have recently discovered the presence of an allosteric site on the CB 1 receptor. Consequently, it may also prove possible to enhance 'autoprotective' effects of released endocannabinoids with CB 1 allosteric enhancers or, indeed, to reduce proposed 'autoimpairing' effects of released endocannabinoids such as excessive food intake with CB 1 allosteric antagonists.

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“…Thus, the present results provide the first definite evidence for the regulatory role of TRPV1 receptors in the long-term inflammatory and hyperalgesic symptoms of the adjuvant arthritis model. Several mediators, such as bradykinin, prostaglandins, protons, histamine, serotonin, nerve growth factor (Ferrell and Lam, 1996;Szolcsanyi et al, 1998a), and endocannabinoids (Gauldie et al, 2001;Baker and McDougall, 2004) released during arthritis have been shown to activate or sensitize the capsaicin-sensitive nerve endings. TRPV1 activation induces the release of inflammatory neuropeptides such as substance P and CGRP, which evoke local plasma protein extravasation, arteriolar vasodilatation Ferrell, 1991, 1993), and stimulate inflammatory cells in the joint.…”

Section: Role Of Trpv1 In Adjuvant-induced Chronic Murine Arthritis 115mentioning

confidence: 99%

Role of Transient Receptor Potential Vanilloid 1 Receptors in Adjuvant-Induced Chronic Arthritis: In Vivo Study Using Gene-Deficient Mice

Szabó

Helyes²,

Sándor³

et al. 2005

J Pharmacol Exp Ther

137

123

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The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel localized on a subset of primary sensory neurons and can be activated by a wide range of stimuli. The present study investigated the role of this receptor in chronic arthritis evoked by complete Freund's adjuvant (CFA) using TRPV1 receptor gene-deleted (TRPV1 Ϫ/Ϫ ) mice and wildtype counterparts (TRPV1 ϩ/ϩ ). In TRPV1 ϩ/ϩ mice, CFA injected intraplantarly into the left hindpaw and the root of the tail induced swelling of the injected and contralateral paws up to 130 and 28%, respectively, measured by plethysmometry throughout 18 days. Mechanonociceptive threshold measured with dynamic plantar aesthesiometry was decreased by 50 and 18% on the injected and contralateral paws, respectively. Histological examination and scoring of the tibiotarsal joints revealed marked arthritic changes in wild-type mice. In TRPV1 Ϫ/Ϫ animals edema, histological score and mechanical allodynia were significantly smaller. Daily treatment with the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the cyclooxygenase inhibitor indomethacin, the bradykinin B2 receptor antagonist

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The cannabinomimetic arachidonyl‐2‐chloroethylamide (ACEA) acts on capsaicin‐sensitive TRPV₁ receptors but not cannabinoid receptors in rat joints

Cited by 44 publications

References 41 publications

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Untitled

The pharmacology of cannabinoid receptors and their ligands: an overview

Role of Transient Receptor Potential Vanilloid 1 Receptors in Adjuvant-Induced Chronic Arthritis: In Vivo Study Using Gene-Deficient Mice

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The cannabinomimetic arachidonyl‐2‐chloroethylamide (ACEA) acts on capsaicin‐sensitive TRPV1 receptors but not cannabinoid receptors in rat joints

Cited by 44 publications

References 41 publications

Untitled

Untitled

The pharmacology of cannabinoid receptors and their ligands: an overview

Role of Transient Receptor Potential Vanilloid 1 Receptors in Adjuvant-Induced Chronic Arthritis: In Vivo Study Using Gene-Deficient Mice

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The cannabinomimetic arachidonyl‐2‐chloroethylamide (ACEA) acts on capsaicin‐sensitive TRPV₁ receptors but not cannabinoid receptors in rat joints