Central and peripheral sites of action for CB2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats
TL;DR: The present study elucidated the CB2 receptor expression in ‘pain relevant’ tissues and the potential sites of action of CB2 agonism in rats to elucidate the mechanisms underlying CB2‐mediated analgesic effects.
Abstract: BACKGROUND AND PURPOSE Cannabinoid CB2 receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB2-mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB2 receptor expression in ‘pain relevant’ tissues and the potential sites of action of CB2 agonism in rats.
EXPERIMENTAL APPROACH Expression of cannabinoid receptor mRNA was evaluated by quantitative RT-PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB2 mediated antinociception were evaluated in vivo following intra-DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB2-selective agonists A-836339 and AM1241.
KEY RESULTS CB2 receptor gene expression was significantly up-regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A-836339 and AM1241 produced dose-dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB2 agonists also produced significant analgesic effects in SNL (intra-DRG and i.t.) and CFA (intra-DRG) pain models. In contrast to A-836339, i.paw administration of AM-1241 dose-relatedly reversed the CFA-induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties.
CONCLUSIONS AND IMPLICATIONS These results demonstrate that both DRG and spinal cord are important sites contributing to CB2 receptor-mediated analgesia and that the changes in CB2 receptor expression play a crucial role for the sites of action in regulating pain perception.
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01 Jan 1999
TL;DR: In this article, anandamide attenuates the pain behavior produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the central nervous system.
Abstract: The potent analgesic effects of cannabis-like drugs and the presence of CB1-type cannabinoid receptors in pain-processing areas of the brain and spinal cord, indicate that endogenous cannabinoids such as anandamide may contribute to the control of pain transmission within the central nervous system (CNS). Here we show that anandamide attenuates the pain behaviour produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. Gas-chromatography/mass-spectrometry measurements indicate that the levels of anandamide and PEA in the skin are enough to cause a tonic activation of local cannabinoid receptors. In agreement with this possibility, the CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These results indicate that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.
918 citations
TL;DR: This review summarizes the present knowledge of CB2 receptor signaling, localization, and regulation, and discusses the availability of genetic tools to study CB2 receptors and also provides an update on preclinical data on CB2 agonists in pain models.
Abstract: The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprising CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor–based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclinical data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data.
214 citations
Cites background from "Central and peripheral sites of act..."
...An interesting biologic property of CB2 receptors is their high inducibility, with CB2 mRNA levels often increasing as much as 100-fold following nerve injury or during inflammation (Maresz et al., 2005; Hsieh et al., 2011)....
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TL;DR: Preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions are examined.
197 citations
Cites background from "Central and peripheral sites of act..."
...Acute administration of CB2 receptor agonists reduces CFA-induced mechanical and thermal hyperalgesia (Hsieh et al, 2011; Valenzano et al, 2005; Yao et al, 2008, 2009)....
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...…administration into a ventral footpad leads to upregulation of CB2 receptors, but not CB2 receptor mRNA in dorsal root ganglia or ipsilateral paw tissue of rats, suggesting that these receptors play an integral role in the endocannabinoid modulation of chronic inflammatory pain (Hsieh et al, 2011)....
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TL;DR: The evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults and calls for larger well-designed studies to determine the long-term efficacy and long- term safety of cannabis/cannabinoids.
Abstract: Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term 'medical cannabis' refers to physician-recommended use of the cannabis plant and its components, called cannabinoids, to treat disease or improve symptoms. Chronic pain is the most commonly cited reason for using medical cannabis. Cannabinoids act via cannabinoid receptors, but they also affect the activities of many other receptors, ion channels and enzymes. Preclinical studies in animals using both pharmacological and genetic approaches have increased our understanding of the mechanisms of cannabinoid-induced analgesia and provided therapeutical strategies for treating pain in humans. The mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neuron excitability, activation of descending inhibitory pain pathways, and reduction of neural inflammation. Recent meta-analyses of clinical trials that have examined the use of medical cannabis in chronic pain present a moderate amount of evidence that cannabis/cannabinoids exhibit analgesic activity, especially in neuropathic pain. The main limitations of these studies are short treatment duration, small numbers of patients, heterogeneous patient populations, examination of different cannabinoids, different doses, the use of different efficacy endpoints, as well as modest observable effects. Adverse effects in the short-term medical use of cannabis are generally mild to moderate, well tolerated and transient. However, there are scant data regarding the long-term safety of medical cannabis use. Larger well-designed studies of longer duration are mandatory to determine the long-term efficacy and long-term safety of cannabis/cannabinoids and to provide definitive answers to physicians and patients regarding the risk and benefits of its use in the treatment of pain. In conclusion, the evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults. Careful follow-up and monitoring of patients using cannabis/cannabinoids are mandatory.
191 citations
TL;DR: The results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.
153 citations
References
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TL;DR: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals.
Abstract: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals. Such studies are essential if new and clinically relevant knowledge about the mechanisms of pain is to be acquired. Investigations in conscious animals intended to stimulate chronic pain in man are being performed. Such experiments require careful planning to avoid or at least minimize pain in the animals.
7,443 citations
"Central and peripheral sites of act..." refers methods in this paper
...…outlined in protocols approved by Abbott Laboratories’ Institutional Animal Care and Use Committee and followed the Guidelines on Ethical Standards for Investigations of Experimental Pain in Conscious Animals laid down by the International Association for the Study of Pain (Zimmermann, 1983)....
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...All testing was done following procedures outlined in protocols approved by Abbott Laboratories’ Institutional Animal Care and Use Committee and followed the Guidelines on Ethical Standards for Investigations of Experimental Pain in Conscious Animals laid down by the International Association for the Study of Pain (Zimmermann, 1983)....
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TL;DR: Threshold measurement using the up-down paradigm, in combination with the neuropathy pain model, represents a powerful tool for analyzing the effects of manipulations of the neuropathic pain state.
6,560 citations
"Central and peripheral sites of act..." refers methods in this paper
...Paw withdrawal threshold (PWT) was determined by using the Dixon’s up–down method (Chaplan et al., 1994)....
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TL;DR: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve and the postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain were produced.
Abstract: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
5,121 citations
"Central and peripheral sites of act..." refers methods in this paper
...…the maximum threshold was equal to 15¥ g. Rat chronic constriction injury (CCI) model of neuropathic pain As previously described in detail by the method of Bennett and Xie (1988), the right common sciatic nerve was isolated at mid-thigh level, and loosely ligated by four chromic gut (5-0) ties…...
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TL;DR: Both the thermal method and the Randall‐Selitto mechanical method detected dose‐related hyperalgesia and its blockade by either morphine or indomethacin, but the Thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
Abstract: A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
4,829 citations
"Central and peripheral sites of act..." refers methods in this paper
...Thermal hyperalgesia was determined using a commercially available thermal paw stimulator (UARDG, University of California, San Diego, CA, USA) as described by Hargreaves et al. (1988)....
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TL;DR: The cloning and expression of a complementary DNA that encodes a G protein-coupled receptor that is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana are suggested.
Abstract: Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
4,806 citations
"Central and peripheral sites of act..." refers background in this paper
...The CB2 receptor shares approximately 44% overall sequence homology with the CB1 receptor and 68% homology within the transmembrane domains Matsuda et al. 1990; Munro et al. 1993)....
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...The cannabinoid receptors belong to the G-protein coupled receptor (GPCR) super family containing seven transmembrane domains (Matsuda et al., 1990; Munro et al., 1993)....
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