Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

Suplita, Richard L.; Gutierrez, Tannia; Fegley, Darren; Piomelli, Daniele; Hohmann, Andrea G.

doi:10.1016/j.neuropharm.2005.10.007

Cited by 69 publications

(69 citation statements)

References 59 publications

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“…Detailed study of this effect revealed the mobilisation of both AEA and 2-AG in the periaqueductal grey matter (111) , and suggested that 2-AG acting at CB 1 receptors was the predominant mechanism. Additional work indicated that further enhancing stress-induced EC signalling via FAAH or MAGL inhibition produces still greater anti-nociceptive effects (112,113) , and confirmed the pivotal role of 2-AG signalling in the periaqueductal grey matter (114) . The involvement of stress in human pain responses and the presence of an EC-mediated mechanism are now being studied clinically (115) .…”

Section: Supra-spinal Mechanismsmentioning

confidence: 75%

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

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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...

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Section: Supra-spinal Mechanismsmentioning

confidence: 75%

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

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“…Footshockinduced endocannabinoid mobilization could produce behavioral sensitization by increasing cannabinoid receptor affinity and/or by facilitating activation of signal transduction pathways. Systemically administered cannabinoids activate spinal as well as supraspinal antinociceptive mechanisms ; these mechanisms could synergize with antinociceptive effects mediated by stress-induced endocannabinoid mobilization Suplita II et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia

et al. 2008

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SummaryFootshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB 1 antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Δ 9 -tetrahydrocannabinol (Δ 9 -THC). The converse was also true; acute Δ 9 -THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Δ 9 -THC. Repeated exposure to footshock (3 min/day for 15 days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans.

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“…141 Stress antinociception was associated with the heightened release of endogenous 2-AG, whereas increases in anandamide mobilization were not detected, 141 perhaps because of greater variability and lower absolute levels of anandamide in these samples. Rimonabant failed to suppress endocannabinoid SIA when administered intrathecally to rats at a dose 10 times greater than that delivered to the PAG and RVM.…”

Section: E703mentioning

confidence: 94%

Endocannabinoid mechanisms of pain modulation

Hohmann

Suplita

2006

AAPS J

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188

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Cannabinoids are antinociceptive in animal models of acute, tissue injury -, and nerve injury -induced nociception. This review examines the biology of endogenous cannabinoids (endocannabinoids) and behavioral, neurophysiological, and neuroanatomical evidence supporting the notion that cannabinoids play a role in pain modulation. Behavioral pharmacological approaches, in conjunction with the identifi cation and quantifi cation of endocannabinoids through the use of liquid and gas chromatography mass spectrometry, have provided insight into the functional roles of en docannabinoids in pain modulation. Here we examine the distribution of cannabinoid receptors and endocannabinoid-hydrolyzing enzymes within pain modulatory circuits to gether with behavioral, neurochemical, and neurophysiological studies that suggest a role for endocannabinoid signaling in pain modulation. This review will provide a comprehensive evaluation of the roles of the endocannabinoids 2-arachidonoylglycerol and anandamide in stress-induced analgesia. These fi ndings provide a functional framework with which to understand the roles of endocannabinoids in nociceptive processing at the supraspinal level.K EYWORDS: 2-arachidonoylglycerol , anandamide , CB1 , fatty acid amide hydrolase , monoacylglycerol lipase , periaqueductal gray , rostral ventromedial medulla

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Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

Cited by 69 publications

References 59 publications

Endocannabinoid system and pain: an introduction

Endocannabinoid system and pain: an introduction

Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia

Endocannabinoid mechanisms of pain modulation

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