Tolerance to morphine microinjections in the periaqueductal gray (PAG) induces tolerance to systemic, but not intrathecal morphine

Siuciak, Judith A.; Advokat, Claire

doi:10.1016/0006-8993(87)91476-4

Cited by 50 publications

(32 citation statements)

References 41 publications

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“…This is known as tolerance, and is particularly notorious for opiates. The PAG is crucial for tolerance to opiates [37,38,39,40,41]. The concept that endogenous opioids are somehow involved when NSAIDs act upon the descending pain control system to cause “analgesia” is supported by the finding in rats that microinjection of metamizol or aspirin twice daily into the PAG, or systemic administration of aspirin, ketorolac or xefocam twice daily, results in tolerance to the NSAID and cross-tolerance to morphine, whether microinjected into the PAG or given systemically [33,42,43].…”

Section: The Descending Pain Control System and Nsaid-induced Tolementioning

confidence: 99%

NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System

2010

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Nonsteroidal anti-inflammatory drugs (NSAIDs) act upon peripheral tissues and upon the central nervous system to produce analgesia. A major central target of NSAIDs is the descending pain control system. The rostral structures of the descending pain control system send impulses towards the spinal cord and regulate the transmission of pain messages. Key structures of the descending pain control system are the periaqueductal gray matter (PAG) and the rostral ventromedial region of the medulla (RVM), both of which are critical targets for endogenous opioids and opiate pharmaceuticals. NSAIDs also act upon PAG and RVM to produce analgesia and, if repeatedly administered, induce tolerance to themselves and cross-tolerance to opioids. Experimental evidence shows that this is due to an interaction of NSAIDs with endogenous opioids along the descending pain control system. Analgesia by NSAIDs along the descending pain control system also requires an activation of the CB1 endocannabinoid receptor. Several experimental approaches suggest that opioids, NSAIDs and cannabinoids in PAG and RVM cooperate to decrease GABAergic inhibition and thus enhance the descending flow of impulses that inhibit pain.

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Section: The Descending Pain Control System and Nsaid-induced Tolementioning

confidence: 99%

NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System

2010

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“…The periaqueductal gray (PAG) is a brain stem area important for the development of opioid tolerance. Direct microinjection of opioids into the PAG produces antinociception (Jacquet and Lajtha, 1976;Bodnar, 2000), and repeated microinjections of morphine into the vlPAG induce tolerance to the antinociceptive effects of morphine (Jacquet and Lajtha, 1976;Siuciak and Advokat, 1987;Morgan et al, 2006). Numerous cellular and molecular adaptations associated with repeated and long-term administration of opioids have been identified in the vlPAG (Ingram et al, 1998(Ingram et al, , 2007Connor et al, 1999a;Bagley et al, 2005a,b), suggesting that changes in -opioid receptor (MOPr) signaling pathways are crucial for the expression of morphine tolerance.…”

Section: Introductionmentioning

confidence: 99%

Tolerance to the Antinociceptive Effect of Morphine in the Absence of Short-Term Presynaptic Desensitization in Rat Periaqueductal Gray Neurons

Fyfe

Cleary

Macey

et al. 2010

J Pharmacol Exp Ther

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Opioids activate the descending antinociceptive pathway from the ventrolateral periaqueductal gray (vlPAG) by both pre-and postsynaptic inhibition of tonically active GABAergic neurons (i.e., disinhibition). Previous research has shown that short-term desensitization of postsynaptic -opioid receptors (MOPrs) in the vlPAG is increased with the development of opioid tolerance. Given that pre-and postsynaptic MOPrs are coupled to different signaling mechanisms, the present study tested the hypothesis that short-term desensitization of presynaptic MOPrs also contributes to opioid tolerance. Twice-daily injections of morphine (5 mg/kg s.c.) for 2 days caused a rightward shift in the morphine dose-response curve on the hot plate test (D 50 ϭ 9.9 mg/kg) compared with saline-pretreated (5.3 mg/kg) male Sprague-Dawley rats. In vitro whole-cell patch-clamp recordings from vlPAG slices revealed that inhibition of evoked inhibitory postsynaptic currents (eIPSCs) by the MOPrselective agonist [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin was decreased in morphine-tolerant (EC 50 ϭ 708 nM) compared with saline-pretreated rats (EC 50 ϭ 163 nM). However, shortterm desensitization of MOPr inhibition of eIPSCs was not observed in either saline-or morphine-pretreated rats. Reducing the number of available MOPrs with the irreversible opioid receptor antagonist, ␤-chlornaltrexamine decreased maximal MOPr inhibition with no evidence of desensitization, indicating that the lack of observed desensitization is not caused by receptor reserve. These results demonstrate that tolerance to the antinociceptive effect of morphine is associated with a decrease in presynaptic MOPr sensitivity or coupling to effectors, but this change is independent of short-term MOPr desensitization.

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“…Recent evidence suggests that the periaqueductal gray (PAG) is particularly important in the development of tolerance to antinociception produced by systemic morphine administration. Repeated microinjection of morphine into the ventrolateral PAG is sufficient to produce tolerance (Tortorici et al, 1999;Morgan et al, 2005a) and crosstolerance develops between systemic and direct PAG administration (Jacquet and Lajtha, 1976;Siuciak and Advokat, 1987;Morgan et al, 2006). Moreover, antinociceptive tolerance to systemic morphine administration is disrupted if the action of morphine is blocked in the ventrolateral PAG (Lane et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

Ingram

Macey

Fossum

et al. 2007

Neuropsychopharmacol

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Tolerance to the pain-relieving effects of opiates limits their clinical use. Although morphine tolerance is associated with desensitization of m-opioid receptors, the underlying cellular mechanisms are not understood. One problem with the desensitization hypothesis is that acute morphine does not readily desensitize m-opioid receptors in many cell types. Given that neurons in the periaqueductal gray (PAG) contribute to morphine antinociception and tolerance, an understanding of desensitization in PAG neurons is particularly relevant. Opioid activity in the PAG can be monitored with activation of G-protein-mediated inwardly rectifying potassium (GIRK) currents. The present data show that opioids have a biphasic effect on GIRK currents in morphine tolerant rats. Opioid activation of GIRK currents is initially potentiated in morphine (EC 50 ¼ 281 nM) compared to saline (EC 50 ¼ 8.8 mM) pretreated rats as indicated by a leftward shift in the concentration-response curve for met-enkephalin (ME)-induced currents. These currents were inhibited by superfusion of the m-opioid receptor antagonist b-funaltrexamine (b-FNA) suggesting that repeated morphine administration enhances agonist stimulation of m-opioid receptor coupling to G-proteins. Although supersensitivity of m-opioid receptors in the PAG is counterintuitive to the development of tolerance, peak GIRK currents from tolerant rats desensitized more than currents from saline pretreated rats (56% of peak current after 10 min compared to 15%, respectively). These data indicate that antinociceptive tolerance may be triggered by enhanced agonist potency resulting in increased desensitization of m-opioid receptors.

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Tolerance to morphine microinjections in the periaqueductal gray (PAG) induces tolerance to systemic, but not intrathecal morphine

Cited by 50 publications

References 41 publications

NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System

NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System

Tolerance to the Antinociceptive Effect of Morphine in the Absence of Short-Term Presynaptic Desensitization in Rat Periaqueductal Gray Neurons

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

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