Morphine-Dependent Rats: Blockade of Precipitated Abstinence by Tetrahydrocannabinol

Hine, Bromfield; Friedman, Eitan; Torrelio, Marina; Gershon, Samuel

doi:10.1126/science.1167428

Cited by 117 publications

(38 citation statements)

References 9 publications

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“…Although the CB 1 agonist CP 55,940 did not prevent MOR-induced cAMP overshoot in SH-SY5Y cells, this may be due to low expression levels. This is pertinent because levels of CB 1 in the brain are generally high, and short-term administration of cannabinoid agonists to morphine-dependent rodents prevented withdrawal symptoms including jumping, weight loss, wet dog shakes, and diarrhea, although the mechanism or site of action was not determined (Hine et al, 1975).…”

Section: Discussionmentioning

confidence: 99%

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

2010

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Organization of G protein-coupled receptors and cognate signaling partners at the plasma membrane has been proposed to occur via multiple mechanisms, including membrane microdomains, receptor oligomerization, and protein scaffolding. Here, we investigate the organization of six types of G i/o -coupled receptors endogenously expressed in SH-SY5Y cells. The most abundant receptor in these cells was the -opioid receptor (MOR), the activation of which occluded acute inhibition of adenylyl cyclase (AC) by agonists to ␦-opioid (DOR), nociceptin/orphanin FQ peptide (NOPr), ol]-enkephalin (DAMGO) also occluded the ability of DOR agonist to stimulate G proteins. However, at lower agonist concentrations and at shorter incubation times when G proteins were not limiting, the relationship between MOR and DOR agonists was additive. The additive relationship was confirmed by isobolographic analysis. Long-term coadministration of MOR and DOR agonists caused cAMP overshoot that was not additive, suggesting that sensitization of AC mediated by these two receptors occurs by a common pathway. Furthermore, heterologous inhibition of AC by agonists to DOR, NOPr, and ␣ 2 AR reduced the expression of cAMP overshoot in DAMGO-dependent cells. However, this cross-talk did not lead to heterologous tolerance. These results indicate that multiple receptors could be tethered into complexes with cognate signaling proteins and that access to shared AC by multiple receptor types may provide a means to prevent opioid withdrawal.

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Section: Discussionmentioning

confidence: 99%

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

2010

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“…Thus, we hypothesize that ⌬ 9 -THC might alter the expression of morphine antinociceptive tolerance and/or dependence. ⌬ 9 -THC reduces naloxone-precipitated withdrawal in morphine-dependent rats and mice (Hine et al, 1975;Bhargava, 1976). The endogenous cannabinoid anandamide also decreases naloxone-precipitated morphine withdrawal (Vela et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ⁹-Tetrahydrocannabinol

Cichewicz

Welch²

2003

J Pharmacol Exp Ther

107

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Previous studies have demonstrated a functional interaction between cannabinoid and opioid systems in the development and expression of morphine tolerance and dependence. In these experiments, we examined the effect of a low oral dose of ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) on the development of oral morphine tolerance and the expression of naloxone-precipitated morphine withdrawal signs of jumping and diarrhea in ICR mice. Chronic treatment with high-dose oral morphine produced a 3.12-fold antinociceptive tolerance. Tolerance to morphine was prevented in groups receiving a daily cotreatment with a nonanalgetic dose (20 mg/kg p.o.) of ⌬ 9 -THC, except when challenged with a very high dose of morphine. The chronic coadministration of low-dose ⌬ 9 -THC also reduced naloxone-precipitated (1 mg/kg s.c.) platform jumping by 50% but did not reduce diarrhea. In separate experiments, mice treated chronically with high-dose morphine p.o. were not cross-tolerant to ⌬ 9 -THC; in fact, these morphine-tolerant mice were more sensitive to the acute antinociceptive effects of ⌬ 9 -THC. ⌬ 9 -THC (20 mg/kg p.o.) also reduced naloxone-precipitated jumping but not diarrhea when administered acutely to morphine-tolerant mice. These results represent the first evidence that oral morphine tolerance and dependence can be circumvented by coadministration of a nonanalgetic dose of ⌬ 9 -THC p.o. In summary, cotreatment with a combination of morphine and ⌬ 9 -THC may prove clinically beneficial in that long-term morphine efficacy is maintained.The clinical use of morphine for long periods of time is limited by its propensity to cause tolerance and physical dependence after repeated administration. To overcome tolerance to the analgesic effects of morphine, higher doses are necessary for adequate pain relief but are often accompanied by undesirable side effects such as constipation, nausea, and respiratory depression (Ellison, 1993). Morphine tolerance has been developed in rodent models using subcutaneously implanted morphine pellets (Cicero and Meyer, 1973;Bhargava, 1978), but little is known about tolerance to oral doses of morphine in mice. Mao et al. (1996) observed a decrease in antinociception produced by oral morphine in rats as measured by the tail-flick test over a period of several days.Our laboratory and others have shown that combinations of cannabinoids with morphine profoundly enhance morphine-induced analgesia. ⌬ 9 -THC at a nonanalgetic dose administered p.o. to mice significantly enhances the potency of opioids such as morphine and codeine (Smith et al., 1998;Cichewicz et al., 1999). This enhancement is theorized to be due to a combination of morphine's direct effects on the -opioid receptor and the effect of endogenous opioids whose release is stimulated by ⌬ 9 -THC (Smith et al., 1994;Pugh et al., 1996). In addition, the CB1 cannabinoid receptor and -opioid receptor have been found to be colocalized in areas important for the expression of morphine abstinence: nucleus accumbens, septum, striatum, periaqueductal ...

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“…Cannabinoids and opioids produce similar behavioral and physiological effects, such as antinociception, hypothermia, and reduced locomotor activity . Both systems seem to be functionally coupled in drug reward and addiction, because opioid withdrawal symptoms were alleviated by cannabinoids (Hine et al, 1975;Lichtman et al, 2001;Yamaguchi et al, 2001) and they were significantly reduced in CB1 receptor knock-out mice (Ledent et al, 1999;Lichtman et al, 2001). CB1 receptor antagonists blocked heroin selfadministration and morphine-induced place preference (MasNieto et al, 2001;Navarro et al, 2001).…”

mentioning

confidence: 99%

“…Key words: cannabinoid; opioid; mice; mutation; withdrawal; addiction; place aversion Pharmacological and genetic evidence suggest important functional interactions between the endogenous brain cannabinoid and opioid systems (Hine et al, 1975;Vela et al, 1995;Pugh et al, 1997;Tanda et al, 1997;Ledent et al, 1999;Manzanares et al, 1999;Valverde et al, 2000Valverde et al, , 2001. Most of the behavioral effects of endogenous cannabinoids (arachidonoyletanolamide, 2-arachidonoylglycerol, and 2-arachidonylglycerol) and ⌬-9-tetrahydrocannabinol (THC) are mediated by cannabinoid CB 1 receptors (Ledent et al, 1999;Zimmer et al, 1999), whereas opioids (endorphin, enkephalins, and dynorphins) act on , ␦, and receptors (Kieffer, 1999).…”

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confidence: 99%

Absence of Δ-9-Tetrahydrocannabinol Dysphoric Effects in Dynorphin-Deficient Mice

et al. 2001

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The involvement of dynorphin on ⌬-9-tetrahydrocannabinol (THC) and morphine responses has been investigated by using mice with a targeted inactivation of the prodynorphin (Pdyn) gene. Dynorphin-deficient mice show specific changes in the behavioral effects of THC, including a reduction of spinal THC analgesia and the absence of THC-induced conditioned place aversion. In contrast, acute and chronic opioid effects were normal. The lack of negative motivational effects of THC in the absence of dynorphin demonstrates that this endogenous opioid peptide mediates the dysphoric effects of marijuana.Key words: cannabinoid; opioid; mice; mutation; withdrawal; addiction; place aversion Pharmacological and genetic evidence suggest important functional interactions between the endogenous brain cannabinoid and opioid systems (Hine et al

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Morphine-Dependent Rats: Blockade of Precipitated Abstinence by Tetrahydrocannabinol

Cited by 117 publications

References 9 publications

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ⁹-Tetrahydrocannabinol

Absence of Δ-9-Tetrahydrocannabinol Dysphoric Effects in Dynorphin-Deficient Mice

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Morphine-Dependent Rats: Blockade of Precipitated Abstinence by Tetrahydrocannabinol

Cited by 117 publications

References 9 publications

Gi/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

Gi/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ9-Tetrahydrocannabinol

Absence of Δ-9-Tetrahydrocannabinol Dysphoric Effects in Dynorphin-Deficient Mice

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G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ⁹-Tetrahydrocannabinol