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9 nor 9β Hydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: comparisons with morphine

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The effects of (+/-)9-nor-9beta-hydroxyhexahydrocannabinol (beta-HHC) on tail-flick test activity and the accumulation of newly synthesized dopamine and norepinephrine were studied in the male albino mouse. The same parameters were also studied in naloxone-pretreated and morphine-tolerant mice. beta-HHC was about equipotent with morphine in the mouse tail-flick (ED50 = 7.12 mg/kg). The cannabinoid also produced dose-dependent increases in the accumulation of newly synthesized DA and NE. Pretreatment with 2 mg/kg of naloxone antagonized both the tail-flick activity and blocked the increases in catecholamine synthesis produced by beta-HHC. Cross-tolerance between beta-HHC and morphine did not exist in regard to either tail-flick activity or increased catecholamine synthesis. These studies suggest that beta-HHC may share some properties with the narcotic analgesics but that significant differences exist. Furthermore, these studies offer further evidence for the involvement of catecholamine containing neurons in the central mediation of the tail-flick response.
... Cannabinoid system is involved in the physiological control of pain (Hasanein et al. 2007;Walker and Huang 2002). Exogenous cannabinoids reduce responsiveness to noxious stimuli in rats and mice with a potency and efficacy similar to that of morphine (Bloom et al. 1977). Many supraspinal sites implicated in the nociception modulation contain cannabinoid receptors (Iversen 2003). ...
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RationaleNucleus cuneiformis (NC), a reticular nucleus of the midbrain, is a part of the descending pain modulatory system and therefore has an important role in pain perception.Objectives Considering the abundance of GABAA and cannabinoid receptors in the NC and also the bidirectional roles for GABA in controlling nociception, the present study examined the effects of bilateral intra-NC microinjection of different doses of the GABAA receptor agonist, muscimol, and the GABAA receptor antagonist, bicuculline, on pain modulation using formalin test. We also assessed interaction between canabinergic and GABAergic systems in the NC during this test.Methods Rats were exposed to intra-NC microinjection of bicuculline (50,100, and 200 ng/side) or muscimol (60, 120, and 240 ng/side) and then subjected to the formalin test. In another set of experiments, the effects of muscimol (60 ng/side) or bicuculline (50 ng/side) administration 5 min before a cannabinoid receptor agonist WIN 55,212-2 (5, 10, and 20 μg/side) microinjection into NC on the formalin test were evaluated.ResultsMicroinjection of bicuculline and muscimol into the NC decreased and increased pain responses, respectively, in a dose-dependent manner during both phases of the test. Microinjection of WIN 55,212-2 into the NC significantly reduced pain responses in a dose-dependent manner. Microinjection of bicuculline or muscimol in combination with WIN 55,212-2 into the NC respectively potentiated and attenuated WIN 55,212-2–induced antinociception in the formalin test.Conclusions This study shows that GABA in the NC is involved in pain modulation and suggests the existence of a GABAA-mediated inhibitory system in the NC on pain control. Furthermore, it seems that the antinociceptive effect of WIN 55,212-2 in the formalin test is mediated partly by the activity of local GABAA receptors in the NC.
... In 1972, 11-hydroxy-THC (20) was identified as the principal metabolite of Δ 9 -THC and demonstrated comparable cannabimimetic potency following intravenous administration (Lemberger et al. 1972). Analgesic potency was retained by the simplified 11-OH-THC analog 9-nor-9β-hydroxyhexahydrocannabinol (HHC, 21) (Bloom et al. 1977). It was possible to establish limited SARs for synthetic phytocannabinoid analogs in animals (Razdan 1986), however, the discovery of CB 1 in 1990 and the development of binding and functional assays facilitated the generation of SARs for hundreds of phytocannabinoid analogs. ...
Chapter
Synthetic cannabinoid receptor agonists (SCRAs) have proliferated as new psychoactive substances (NPS) over the past decade. Relative to other classes of NPS, SCRAs are structurally heterogeneous; however, most SCRAs act as potent, high-efficacy agonists of cannabinoid type 1 and type 2 receptors (CB1 and CB2, respectively). Characterization of the pharmacology and toxicology of these substances is hindered by the dynamic nature of the SCRA marketplace. Beyond basic pharmacological profiling at CB1 and CB2 receptors, very little is known about the acute or chronic effects of SCRAs. Many of the effects of SCRAs are qualitatively similar to those of the Δ⁹-tetrahydrocannabinol (Δ⁹-THC) found in cannabis. However, unlike Δ⁹-THC, SCRAs are frequently associated with serious adverse effects, including cardiotoxicity, nephrotoxicity, and death. This chapter will provide an overview of the structure and function of the primary target for SCRAs, the CB1 receptor, and survey the structure-activity relationships of the historical SCRAs that served as templates for the earliest generations of NPS.
... The objective of this study was to examine if action video games have the potential to artificially evoke SIA. Artificially inducing this phenomenon in patients who are about to undergo painful medical procedures could prove to be an effective pain reliever without, or in conjunction with, the use of other exogenous pain relievers (Bloom, Dewey, Harris, & Brosius, 1977;Ford & Finn, 2008). However, this method of potential pain management would only be effective for short periods of time. ...
... Alternatively, THC administered SC and PO had relatively poor activity in the tail-flick test. Regarding SC THC, Bloom et al. (2) also observed only 17% MPE with a large dose of THC (100 mg/kg), and Buxbaum (3) reported only a doubling of latency above baseline. However, others report that THC administered SC was sufficiently efficacious for calculation of ED 50 values (20,22). ...
... In acute pain models, systemic administration of cannabinoids produced an analgesic effect with an efficacy similar to that of opioids (Walker et al., 2001), and was even more effective than opioids in some chronic pain models (Bloom et al., 1977;Tsou et al., 1996). These analgesic effects are mediated by both central CB 1 (Hohmann et al., 1995;Tsou et al., 1996;Hohmann et al., 1999a) and peripheral CB 1 (Agarwal et al., 2007) and CB 2 (Calignano et al., 1998;Richardson et al., 1998b) receptors. ...
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Marijuana has been used to relieve pain for centuries. The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2 ) two decades ago. The subsequent identification of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and their biosynthetic and degradation enzymes discloses the therapeutic potential of compounds targeting the endocannabinoid system for pain control. Inhibitors of the anandamide and 2-AG degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, respectively, may be superior to direct cannabinoid receptor ligands as endocannabinoids are synthesized on demand and rapidly degraded, focusing action at generating sites. Recently, a promising strategy for pain relief was revealed in the periaqueductal gray (PAG). It is initiated by Gq -protein-coupled receptor (Gq PCR) activation of the phospholipase C-diacylglycerol lipase enzymatic cascade, generating 2-AG that produces inhibition of GABAergic transmission (disinhibition) in the PAG, thereby leading to analgesia. Here, we introduce the antinociceptive properties of exogenous cannabinoids and endocannabinoids, involving their biosynthesis and degradation processes, particularly in the PAG. We also review recent studies disclosing the Gq PCR-phospholipase C-diacylglycerol lipase-2-AG retrograde disinhibition mechanism in the PAG, induced by activating several Gq PCRs, including metabotropic glutamatergic (type 5 metabotropic glutamate receptor), muscarinic acetylcholine (M1/M3), and orexin 1 receptors. Disinhibition mediated by type 5 metabotropic glutamate receptor can be initiated by glutamate transporter inhibitors or indirectly by substance P, neurotensin, cholecystokinin and capsaicin. Finally, the putative role of 2-AG generated after activating the above neurotransmitter receptors in stress-induced analgesia is discussed.
Chapter
The human cannabinoid receptor, CB1, has been difficult to purify in a functional form, hampering structural and biophysical studies. Here, we present our approaches for obtaining pure, detergent solubilized, functional CB1. We also discuss our site-directed fluorescence labeling (SDFL) methods for identifying different structural changes that CB1 can undergo upon binding different cannabinoid ligands. To identify optimal CB1 constructs for these studies (those with the best expression levels, solubility in detergent and function), we first screened various CB1-green fluorescent protein chimeras in a mammalian expression system. Once identified, we then tagged the best candidates with the 1D4 epitope (the C-terminus of rhodopsin) and purified them using a single-step immunoaffinity process. The resulting, highly pure proteins retain their ability to activate G-protein, and are ~ 85% functional, as assessed by radioligand binding studies. The SDFL studies involve introducing single cysteine residues at key places in the receptor, then labeling them with a small fluorophore, bimane. The spectral properties of the bimane probe are then monitored before and after addition of cannabinoid ligands. Changes in fluorescence of the attached probe indicate regions of the receptor undergoing conformational changes upon ligand binding. Together, these approaches set the stage for a deeper understanding of the structure and function of CB1. Access to pure, functional CB1 makes subsequent structural studies possible (such as crystallography and single-particle EM analysis), and the SDFL studies enable a better structural and mechanistic understanding of this key receptor and the dynamic changes it undergoes during activation and attenuation.
Chapter
Cannabis has been used as medicine and for its mind-altering qualities for centuries.
Article
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 identification and quantification of endocannabinoids through the use of liquid and gas chromatography mass spectrometry, have provided insight into the functional roles of endocannabinoids in pain modulation. Here we examine the distribution of cannabinoid receptors and endocannabinoid-hydrolyzing enzymes within pain modulatory circuits together 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 findings provide a functional framework with which to understand the roles of endocannabinoids in nociceptive processing at the supraspinal level.
Chapter
The biological actions of cannabinoid compounds in humans have received the attention of several excellent reviews within the last 20 years (Abood & Martin, 1992; Bhargava, 1978; Dewey, 1986; Hollister, 1986; Lemberger, 1980; Paton, 1975). It is now believed that many of the effects of cannabimimetic compounds can be attributed to their actions via two receptors, the CB1 and the CB2 cannabinoid receptors. The central nervous system (CNS) responses to cannabinoid compounds are believed to be mediated by the CB1 subtype. The CB1 subtype also exists as a splice variant isoform, CB1(b), which is truncated at an extracellular site and whose mRNA is found in much lower abundance (Rinaldi-Carmona et al, 1996; Shire et al, 1995). The CB1(a) and CB1(b) isoforms exhibit relatively similar pharmacological properties when expressed in Chinese hamster ovary (CHO) cells (Rinaldi-Carmona et al, 1996). The CB1 receptor is a G protein coupled receptor that inhibits adenylate cyclase activity and regulates ion channels. Several recent reviews have described the pharmacology, biochemistry, and CNS distribution of this receptor subtype (Abood & Martin, 1992; Howlett, Bidaut-Russell, et al, 1990; Howlett, Evans, & Houston, 1992; R. Pertwee, 1993). The CB2 receptor is found in immune tissue, and is also a G protein coupled receptor that mediates inhibition of cyclic AMP synthesis. As discussed in reviews by Howlett (1995a), Martin (1986), and Pertwee (1988), certain in vitro effects of cannabinoid drugs have been reported that may not be mediated by a receptor mechanism.
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Behavioral changes, reaction times in analgesic tests and effects on metabolism of cerebral serotonin (5 HT) were monitored in male Sprague-Dawley rats following the administration ofδ 9-tetrahydrocannabinol (THC) as a propylene glycol-serum complex. THC (5.5 mg/kg i.p. and 1.0 mg/kg i.v.) produced characteristic and reproducible behavioral effects, including catalepsy and squealing, as well as significant increases in the reaction time as determined in both the hot plate and tail flick tests for analgesia. Intraventricular injection of THC caused many of the changes seen after systemic administration of the drug. The levels of 5 HT and its principle metabolite, 5-hydroxyindoleacetic acid (5 HIAA) were measured in forebrain and brainstem following THC. No significant change in the level of either indole was observed. Moreover, THC did not alter the turnover of cerebral 5 HT as determined by the probenecid method and did not change the increase in 5 HT following the administration of pargyline. It may thus be concluded that doses of THC which produce significant and reproducible behavioral modifications do not alter the dynamics of the cerebral serotonergic system.
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2-Dimethylallyl- 5,9-dimethyl-2'-hydroxybenzomorphan (Win 20,228) was found to be a weak antagonist of morphine and meperidine, whereas 2-allyl-5-ethyl-2'- hydroxy-9-methyl-6,7-benzomorphan (Win 19,362) and 2-allyl-2'-hydroxy-5,9- dimethyl-6,7-benzomorphan (Win 19,631) were about three times as potent as nalorphine. Preliminary clinical trials indicate that Win 19,362 is about twice as potent as morphine as an analgesic but, like nalorphine, is capable of producing severe psychic side effects. Win 20,228 is estimated to be about half as active as morphine as an analgesic, but no bizarre psychic effects were reported at any dose tested. Studies of addiction liability with Win 20,228 in monkeys suggest that this compound will not support morphine addiction.