Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats

Petrosino, Stefania; Palazzo, Enza; Novellis, Vito de; Bisogno, Tiziana; Rossi, Francesco; Maione, Sabatino; Marzo, Vincenzo Di

doi:10.1016/j.neuropharm.2006.08.011

Cited by 204 publications

(151 citation statements)

References 44 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…In comparison, 2-AG levels were elevated at time-points coinciding with the appearance of glial cell activation and up-regulation of CB 2 receptors, suggesting a temporal segregation of AEA and 2-AG signalling. In agreement with these data, spinal levels of AEA are significantly elevated at early time-points in the chronic constriction injury (neuropathic pain model) model of neuropathic pain in mice (98) . Spinal administration of URB597 reduced mechanically evoked responses of wide dynamic range neurones in rats that underwent spinal nerve ligation and this effect was blocked by preadministration of a CB 1 selective receptor inverse agonist/antagonist (99) .…”

Section: Spinal Mechanismssupporting

confidence: 80%

“…Elevated levels of EC in the periaqueductal grey matter and dorsal raphe nucleus have been observed at 3 and 7 d in the chronic constriction injury model of neuropathic pain (98) . Interestingly, desensitisation of CB 1 receptors in a pain-related cortical brain region has been described in this model at 10 d, when nociceptive behaviour is maximal (117) .…”

Section: Supra-spinal Mechanismsmentioning

confidence: 93%

See 1 more Smart Citation

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

View full text Add to dashboard Cite

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...

show abstract

Section: Spinal Mechanismssupporting

confidence: 80%

Section: Supra-spinal Mechanismsmentioning

confidence: 93%

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

View full text Add to dashboard Cite

show abstract

“…It is also likely that, after CB 1 receptor blockade by the antagonist, the released endocannabinoids could induce antinociception by affecting other pain transmission mechanisms. Recent findings showing an up-regulation of endocannabinoids (anandamide and 2-arachidonoylglycerol) in neuropathic pain models (27) and findings showing this in turn could cause the desensitization of transient receptor potential vanilloid type I leading to blockade of pain transmission (28) would support such a hypothesis.…”

Section: Resultsmentioning

confidence: 93%

Hemopressin is an inverse agonist of CB ₁ cannabinoid receptors

Heimann

Gomes

Dale

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

226

240

View full text Add to dashboard Cite

To date, the endogenous ligands described for cannabinoid receptors have been derived from membrane lipids. To identify a peptide ligand for CB 1 cannabinoid receptors, we used the recently described conformation-state sensitive antibodies and screened a panel of endogenous peptides from rodent brain or adipose tissue. This led to the identification of hemopressin (PVNFKFLSH) as a peptide ligand that selectively binds CB 1 cannabinoid receptors. We find that hemopressin is a CB 1 receptor-selective antagonist, because it is able to efficiently block signaling by CB 1 receptors but not by other members of family A G protein-coupled receptors (including the closely related CB2 receptors). Hemopressin also behaves as an inverse agonist of CB 1 receptors, because it is able to block the constitutive activity of these receptors to the same extent as its well characterized antagonist, rimonabant. Finally, we examine the activity of hemopressin in vivo using different models of pain and find that it exhibits antinociceptive effects when administered by either intrathecal, intraplantar, or oral routes, underscoring hemopressin's therapeutic potential. These results represent a demonstration of a peptide ligand for CB 1 cannabinoid receptors that also exhibits analgesic properties. These findings are likely to have a profound impact on the development of novel therapeutics targeting CB 1 receptors.

show abstract

“…In mice, CCI caused increased AEA and 2-AG levels in the spinal cord, PAG, rostral ventromedial medulla, and dorsal raphe magnus 7 days post-surgery (47). Spinal nerve ligation produced mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paw, accompanied with increased AEA and 2-AG levels in the ipsilateral dorsal root ganglia (48).…”

Section: Neuropathic Painmentioning

confidence: 93%

Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation

Schlosburg

Kinsey

Lichtman

2009

AAPS J

144

112

View full text Add to dashboard Cite

Abstract. The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB 1 and CB 2 cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and antiinflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as Δ 9 -tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB 1 and/or CB 2 receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.KEY WORDS: anandamide; CB 1 cannabinoid receptor; CB 2 cannabinoid receptor; endogenous cannabinoid; fatty acid amide hydrolase (FAAH); inflammatory pain; neuropathic pain.

show abstract

Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats

Cited by 204 publications

References 44 publications

Endocannabinoid system and pain: an introduction

Endocannabinoid system and pain: an introduction

Hemopressin is an inverse agonist of CB ₁ cannabinoid receptors

Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation

Contact Info

Product

Resources

About

Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats

Cited by 204 publications

References 44 publications

Endocannabinoid system and pain: an introduction

Endocannabinoid system and pain: an introduction

Hemopressin is an inverse agonist of CB 1 cannabinoid receptors

Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation

Contact Info

Product

Resources

About

Hemopressin is an inverse agonist of CB ₁ cannabinoid receptors