Dissociation of Tolerance and Dependence for Opioid Peripheral Antinociception in Rats

Aley, K. O.; Levine, Jon D.

doi:10.1523/jneurosci.17-10-03907.1997

Cited by 42 publications

(21 citation statements)

References 33 publications

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“…As reported previously (Aley and Levine, 1997b), we found that NO seems to be involved in tolerance, whereas PKC seems to be involved in dependence (Aley and Levine, 1997b). We have now shown that these systems are involved in development but not at all in expression or in conjunction with other systems for expression.…”

Section: Discussionsupporting

confidence: 84%

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Aley

Levine

1997

J. Neurosci.

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The -opioid [D-Ala 2 ,N-Me-Phe 4 ,Gly-ol 5 ]-enkephalin (DAMGO) exerts a peripheral antinociceptive effect against prostaglandin E 2 (PGE 2 )-induced mechanical hyperalgesia in the hindpaw of the rat. Tolerance and dependence develop to this effect. We have shown previously that tolerance and dependence can be dissociated and are mediated by different second messenger systems. In the present study, we evaluated whether the same or different second messenger systems mediate the development of this peripheral opioid tolerance or dependence compared with the expression of the loss of antinociceptive effect or rebound opioid antagonist hyperalgesia (i.e., expression of tolerance and dependence). DAMGO-induced tolerance was prevented by pretreatment with the nitric oxide synthase inhibitor N G -methyl-L-arginine (NMLA) but not by the protein kinase C (PKC) inhibitor chelerythrine, the adenylyl cyclase inhibitor 2Ј,5Ј-dideoxyadenosine (ddA), or the calcium chelators 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester (TMB-8) and 2-[(2-bis-[carboxymethyl]amino-5-methylphenoxy)-methyl]-6-methoxy-8-bis[carboxymethyl]aminoquinoline (Quin-2).Once established, however, expression of DAMGO tolerance was acutely reversed by TMB-8 or Quin-2 but not by chelerythrine or NMLA. In contrast, naloxone-precipitated hyperalgesia in DAMGO-tolerant paws, a measure of dependence, was blocked by pretreatment with chelerythrine but not by NMLA, ddA, TMB-8, or Quin-2. Naloxone-precipitated hyperalgesia in DAMGO-tolerant paws was acutely reversed by chelerythrine, ddA, TMB-8, or Quin-2 but not by NMLA. Taken together, these results provide the first evidence that different mechanisms mediate the development and expression of both tolerance and dependence to the peripheral antinociceptive effect of DAMGO. However, although the development of tolerance and dependence are entirely separable, the expression of tolerance and dependence shares common calcium-dependent mechanisms. Opioids, which traditionally are thought to produce analgesia by actions in the C NS, also have antinociceptive actions in the periphery (Levine and Taiwo, 1989;Stein, 1991;Stein et al., 1995). Peripheral analgesic effects of opioids seem to be mediated via -opioid receptors and a G i -and G o -protein-mediated inhibition of the cAM P second messenger system in primary afferent nociceptors (Levine and Taiwo, 1989). We and others have reported previously that tolerance and dependence develop for this peripheral antinociceptive effect of -opioid agonists (Aley et al., 1995;Kolesnikov et al., 1996). In the C NS a number of intracellular pathways have been suggested to play a role in opioid tolerance and dependence (Honore et al., 1997). Among these, Ca 2ϩ (Wang et al., 1996), protein kinase C (Mao et al., 1995a,b;Narita et al., 1995), and nitric oxide (Herman et al., 1995;Pasternak et al., 1995;Vaupel et al., 1995;Dambisya and Lee, 1996;Dunbar and Yaksh, 1996) have been most thoroughly implicated. The mechanisms underlying peripheral opioid tolerance and dependence are...

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Section: Discussionsupporting

confidence: 84%

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Aley

Levine

1997

J. Neurosci.

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“…Alternatively, the results of Experiments 1 and 3 may suggest that morphine tolerance and dependence can be separated, at least at the level of glutamatergic neurotransmission. This has been earlier shown in behavioral (Rahman et al, 1994;Paronis and Woods, 1997a, b;Gold et al, 1994) and neurochemical (Lang and Schulz, 1989;Gudehithlu and Bhargava, 1996;Aley and Levine, 1997) studies and experiments with the use of genetically modified mice (Kest et al, 2001;Bohn et al, 2000).…”

Section: Effects Of Gcp II Inhibition On Morphine Dependence/ Withdrawalsupporting

confidence: 55%

Morphine Tolerance and Reward but not Expression of Morphine Dependence are Inhibited by the Selective Glutamate Carboxypeptidase II (GCP II, NAALADase) Inhibitor, 2-PMPA

Popik

Kozela

Wróbel

et al. 2002

Neuropsychopharmacol

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Inhibition of glutamate carboxypeptidase II (GCP II; NAALADase) produces a variety of effects on glutamatergic neurotransmission. The aim of this study was to investigate effects of GCP II inhibition with the selective inhibitor, 2-PMPA, on: (a) development of tolerance to the antinociceptive effects, (b) withdrawal, and (c) conditioned reward produced by morphine in C57/Bl mice. The degree of tolerance was assessed using the tail-flick test before and after 6 days of twice daily (b.i.d.) administration of 2-PMPA and 10 mg/kg of morphine. Opioid withdrawal was measured 3 days after twice daily morphine (30 or 10 mg/kg) administration, followed by naloxone challenge. Conditioned morphine reward was investigated using conditioned place preference with a single morphine dose (10 mg/kg). High doses of 2-PMPA inhibited the development of morphine tolerance (resembling the effect of 7.5 mg/kg of the NMDA receptor antagonist, memantine) while not affecting the severity of withdrawal. A high dose of 2-PMPA (100 mg/kg) also significantly potentiated morphine withdrawal, but inhibited both acquisition and expression of morphine-induced conditioned place preference. Memantine inhibited the intensity of morphine withdrawal as well as acquisition and expression of morphine-induced conditioned place preference. In addition, 2-PMPA did not affect learning or memory retrieval in a simple two-trial test, nor did it produce withdrawal symptoms in morphinedependent, placebo-challenged mice. Results suggest involvement of GCP II (NAALADase) in phenomena related to opioid addiction.

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“…Although 3 hourly intradermal injections of the highly selective MOR agonist DAMGO (1 g) had no effect on nociceptive threshold (Aley et al, 1995;Aley and Levine, 1997a), injection of a fourth dose 1 h later induced mechanical hyperalgesia (Fig. 1A).…”

Section: Distinguishing a Novel Type Of Hyperalgesic Primingmentioning

confidence: 95%

“…We have shown previously that, whereas a single injection of the selective MOR agonist DAMGO alone has no effect on nociceptive threshold and attenuates the mechanical hyperalgesia induced by PGE 2 (Levine and Taiwo, 1989;Taiwo and Levine, 1990), when injected repeatedly, it produces changes in nociceptor function such as tolerance, no longer producing an antihyperalgesic effect and producing mechanical hyperalgesia by itself (Aley et al, 1995;Aley and Levine, 1997a). The repeated injection of DAMGO also induces a latent state of hyperresponsiveness to subsequent injection of proalgesic mediators , here referred to as type II hyperalgesic priming.…”

Section: Figurementioning

confidence: 99%

Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

Araldi

Ferrari

Levine

2015

Journal of Neuroscience

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147

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The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E 2 (PGE 2 ) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNF␣, NGF, or IL-6 receptor) or direct activation of protein kinase C (PKC), the pronociceptive effects of PGE 2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKC, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor.

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Dissociation of Tolerance and Dependence for Opioid Peripheral Antinociception in Rats

Cited by 42 publications

References 33 publications

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Morphine Tolerance and Reward but not Expression of Morphine Dependence are Inhibited by the Selective Glutamate Carboxypeptidase II (GCP II, NAALADase) Inhibitor, 2-PMPA

Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

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