Tag Archives: pain

Targeting cannabinoid agonists for inflammatory and neuropathic pain.

Posted on by
Reply

Abstract

“The cannabinoid receptors CB(1) and CB(2) are class A G-protein-coupled receptors. It is well known that cannabinoid receptor agonists produce relief of pain in a variety of animal models by interacting with cannabinoid receptors. CB(1) receptors are located centrally and peripherally, whereas CB(2) receptors are expressed primarily on immune cells and tissues. A large body of preclinical data supports the hypothesis that either CB(2)-selective agonists or CB(1) agonists acting at peripheral sites, or with limited CNS exposure, will inhibit pain and neuroinflammation without side effects within the CNS. There has been a growing interest in developing cannabinoid agonists. Many new cannabinoid ligands have been synthesized and studied covering a wide variety of novel structural scaffolds. This review focuses on the present development of cannabinoid agonists with an emphasis on selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists for treatment of inflammatory and neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/17594182

Cannabinoid receptors and pain.

Posted on by
Reply

Abstract

“Mammalian tissues contain at least two types of cannabinoid receptor, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB(2) receptors occur centrally and peripherally in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this ‘endocannabinoid system’ has prompted the development of a range of novel cannabinoid receptor agonists and antagonists, including several that show marked selectivity for CB(1) or CB(2) receptors. It has also been paralleled by a renewed interest in cannabinoid-induced antinociception. This review summarizes current knowledge about the ability of cannabinoids to produce antinociception in animal models of acute pain as well as about the ability of these drugs to suppress signs of tonic pain induced in animals by nerve damage or by the injection of an inflammatory agent. Particular attention is paid to the types of pain against which cannabinoids may be effective, the distribution pattern of cannabinoid receptors in central and peripheral pain pathways and the part that these receptors play in cannabinoid-induced antinociception. The possibility that antinociception can be mediated by cannabinoid receptors other than CB(1) and CB(2) receptors, for example CB(2)-like receptors, is also discussed as is the evidence firstly that one endogenous cannabinoid, anandamide, produces antinociception through mechanisms that differ from those of other types of cannabinoid, for example by acting on vanilloid receptors, and secondly that the endocannabinoid system has physiological and/or pathophysiological roles in the modulation of pain.”

http://www.ncbi.nlm.nih.gov/pubmed/11164622

Cannabinoid type 2 receptor as a target for chronic – pain.

Posted on by
1

Abstract

“Availability of selective pharmacological tools enabled a great advance of our knowledge of cannabinoid receptor 2 (CB2) role in pathophysiology. In particular CB2 emerged as an interesting target for chronic pain treatment as demonstrated by several studies on inflammatory and neuropathic preclinal pain models. The mechanisms at the basis of CB2-mediated analgesia are still controversial but data are pointing out in two main directions: an effect on inflammatory cells and/or an action on nociceptors and spinal cord relay centers. In this review will be described the second messenger pathways activated by CB2 agonists, the data underpinning the analgesic profile of CB2 selective agonists and the mechanisms invoked to explain their analgesic action. Finally the ongoing clinical trials and the potential issues for the development of a CB2 agonist drug will be examined.”

http://www.ncbi.nlm.nih.gov/pubmed/19149657

Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain.

Posted on by
Reply

Abstract

“The endocannabinoid system consists of cannabinoid CB(1) and CB(2) receptors, endogenous ligands and their synthesising/metabolising enzymes. Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive information. The analgesic effects of cannabinoids have been well documented. The usefulness of nonselective cannabinoid agonists can, however, be limited by psychoactive side effects associated with activation of CB(1) receptors. Following the recent evidence for CB(2) receptors existing in the nervous system and reports of their up-regulation in chronic pain states and neurodegenerative diseases, much research is now aimed at shedding light on the role of the CB(2) receptor in human disease. Recent studies have demonstrated anti-nociceptive effects of selective CB(2) receptor agonists in animal models of pain in the absence of CNS side effects. This review focuses on the analgesic potential of CB(2) receptor agonists for inflammatory, post-operative and neuropathic pain states and discusses their possible sites and mechanisms of action”

http://www.ncbi.nlm.nih.gov/pubmed/17952647

Targeting CB2 receptors and the endocannabinoid system for the treatment of pain.

Posted on by
1

Abstract

“The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential “partners” for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.”

http://www.ncbi.nlm.nih.gov/pubmed/19150370

CB2 cannabinoid receptor agonists: pain relief without psychoactive effects?

Posted on by
Reply

Abstract

“Cannabinoid receptor agonists significantly diminish pain responses in animal models; however, they exhibit only modest analgesic effects in humans. The relative lack of efficacy in man may be because of the dose limitations imposed by psychoactive side effects. Cannabinoid agonists that selectively target CB(2) (peripheral) cannabinoid receptors should be free of psychoactive effects, perhaps allowing for more effective dosing. CB(2) receptor activation inhibits acute, inflammatory and neuropathic pain responses in animal models. In preclinical studies, CB(2) receptor agonists do not produce central nervous system effects. Therefore, they show promise for the treatment of acute and chronic pain without psychoactive effects.”

http://www.ncbi.nlm.nih.gov/pubmed/12550743

Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors.

Posted on by
Reply

“BACKGROUND:

Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia.”

“CONCLUSIONS:

Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/14508331

Inhibition of pain responses by activation of CB(2) cannabinoid receptors.

Posted on by
1

Abstract

“Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence demonstrates that CB(1) cannabinoid receptor activation inhibits pain responses. Recently, the synthesis of CB(2) cannabinoid receptor-selective agonists has allowed testing whether CB(2) receptor activation inhibits pain. CB(2) receptor activation is sufficient to inhibit acute nociception, inflammatory hyperalgesia, and the allodynia and hyperalgesia produced in a neuropathic pain model. Studies using site-specific administration of agonist and antagonist have suggested that CB(2) receptor agonists inhibit pain responses by acting at peripheral sites. CB(2) receptor activation also inhibits edema and plasma extravasation produced by inflammation. CB(2) receptor-selective agonists do not produce central nervous system (CNS) effects typical of cannabinoids retaining agonist activity at the CB(1) receptor. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise for the treatment of pain and inflammation without CNS side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/12505700

CB2 cannabinoid receptor-mediated peripheral antinociception.

Posted on by
Reply

  “Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB(1) receptor in the production of antinociception. However, the capacity of CB(2) receptors, which are located outside the central nervous system (CNS), to produce antinociception is not known. Using AM1241, a CB(2) receptor-selective agonist, we demonstrate that CB(2) receptors produce antinociception to thermal stimuli… Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise clinically for the treatment of pain without CNS cannabinoid side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/11514083

CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids.

Posted on by
1

  “CB(2) cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB(2) receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB(2) receptors in the normal CNS…

We have demonstrated that antinociception produced by CB2 receptor-selective agonists may be mediated by stimulation of β-endorphin release from CB2-expressing cells. The β-endorphin released thus appears to act at μ-opioid receptors, probably on the terminals of primary afferent neurons, to produce peripheral antinociception. This mechanism allows for the local release of endogenous opioids limited to sites where CB2 receptors are present, thereby leading to anatomical specificity of opioid effects. In this way, CB2 receptor activation may produce peripheral antinociception without CNS side effects.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC549497/