Analgesic tolerance to microinjection of the μ-opioid agonist DAMGO into the ventrolateral periaqueductal gray

Meyer, Paul J.; Fossum, Erin N.; Ingram, Susan; Morgan, Michael M.

doi:10.1016/j.neuropharm.2007.03.002

Cited by 22 publications

(28 citation statements)

References 38 publications

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“…The tolerance liability of an opioid agonist is believed to be inversely related to its ability to internalize the MOP-opioid receptor [33] ; low-efficacy agonists, such as morphine, are poor internalizing agents, while DAMGO and other high-efficacy MOP agonists result in substantial receptor internalization. In contrast, this study and others [12,34] have found that pronounced tolerance occurs following repeated administration of DAMGO into the vlPAG.…”

Section: Discussioncontrasting

confidence: 94%

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The Functional Antiopioid Action of the Ventrolateral Periaqueductal Gray Nociceptin/Orphanin FQ and Nociceptin Receptor System Underlies DAMGO Analgesic Tolerance

Parenti

Scoto²

2010

Pharmacology

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Nociceptin/Orphanin FQ (N/OFQ) counteracts supraspinal opioid effects and plays a role in antinociceptive morphine tolerance. Therefore, in the present study, the selective µ-opioid agonist [D-Ala²-NMe-Phe⁴-Gly-ol⁵]-enkephalin (DAMGO) was used. Repeated injection of DAMGO (1 µg/ 1 µl) into the ventrolateral periaqueductal gray (vlPAG), a key site for the development of opioid tolerance, induced analgesia that lasted up to 3 days. In DAMGO-tolerant rats, injection of the N/OFQ antagonist (±)-J 113397 (4 µg/1 µl), into the same site, restored the antinociceptive effect of DAMGO. If (±)-J 113397 treatment preceded each DAMGO injection, tolerance did not develop. Inhibition of N/OFQ signaling can reverse and prevent the development of DAMGO tolerance in the vlPAG. The results confirm that N/OFQ acts as a functional opioid antagonist.

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Section: Discussioncontrasting

confidence: 94%

“…These results indicate that similar mechanisms likely underlie tolerance to morphine and DAMGO within the PAG [12] .…”

mentioning

confidence: 57%

The Functional Antiopioid Action of the Ventrolateral Periaqueductal Gray Nociceptin/Orphanin FQ and Nociceptin Receptor System Underlies DAMGO Analgesic Tolerance

Parenti

Scoto²

2010

Pharmacology

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“…Nociception was assessed using the hot-plate test 15 min after each injection. This procedure has been shown to produce reliable dose-response curves (Morgan et al, , 2006Meyer et al, 2007).…”

Section: Microinjectionsmentioning

confidence: 99%

Extracellular Signal-Regulated Kinase 1/2 Activation Counteracts Morphine Tolerance in the Periaqueductal Gray of the Rat

Macey

Bobeck

Hegarty

et al. 2009

J Pharmacol Exp Ther

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Repeated administration of opioids produces long-lasting changes in -opioid receptor (MOR) signaling that underlie behavioral changes such as tolerance. Mitogen-activated protein kinase (MAPK) pathways, including MAPK extracellular signal-regulated kinases (ERK1/2), are modulated by opioids and are known to produce long-lasting changes in cell signaling. Thus, we tested the hypothesis that ERK1/2 activation contributes to the development and/or expression of morphine tolerance mediated by the periaqueductal gray (PAG). Changes in phosphorylated ERK1/2 expression were assessed with confocal microscopy and compared to behavioral measures of tolerance to the antinociceptive effects of chronic morphine administration. Repeated microinjection of morphine into the PAG produced tolerance and caused a significant increase in ERK1/2 phosphorylation, an effect not evident with acute morphine microinjection. Microinjection of the MAPK/ERK kinase inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene ethanolate (U0126), into the PAG had no effect on antinociception produced by acute morphine administration. However, repeated coadministration of U0126 and morphine into the PAG blocked ERK1/2 phosphorylation and enhanced the development of morphine tolerance. Coadministration of U0126 with morphine only on the test day also enhanced the expression of morphine tolerance. Administration of the irreversible opioid receptor antagonist ␤-chlornaltrexamine blocked the activation of ERK1/2 caused by repeated morphine microinjections, demonstrating that ERK1/2 activation was a MOR-mediated event. In summary, these studies show that chronic morphine administration alters ERK1/2 signaling and that disruption of ERK1/2 signaling enhances both the development and expression of morphine tolerance. Contrary to expectations, these data indicate that ERK1/2 activation opposes the development of morphine tolerance.Opioid receptor activation results in both acute and longterm changes in neuronal physiology. Tolerance, defined as a decrease in agonist potency with repeated administration, is an example of a long-term change caused by opioids. Although tolerance to the antinociceptive effect of morphine develops rapidly with repeated opioid administration (Bailey and Connor, 2005), the signaling mechanism underlying the loss of potency has not been elucidated. One problem with identifying the mechanism is that -opioid receptor (MOR) signaling is coupled to several downstream effectors, including inhibition of adenylyl cyclase, activation of K ϩ channels, inhibition of Ca 2ϩ channels, and activation of p42/44 mitogen-activated protein kinases (MAPK) (Spencer et al., 1997;Standifer and Pasternak, 1997;Williams et al., 2001).MAPK extracellular signal-regulated kinases (ERK1/2) are prime candidates for the cellular mechanism underlying tolerance because they are known to contribute to synaptic

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“…The PAG is a mediator of opioid analgesia 43, 54, 78 , and MORs are expressed by vlPAG-RVM projection neurons 59 . As nAChR s and MORs have opposing effects on excitability, we hypothesized non-overlapping distribution of these receptors among vlPAG projection neurons.…”

Section: Resultsmentioning

confidence: 99%

“…PNU-120596 and PHA-543613 concentrations were determined empirically in pilot testing, as this is the first study conducting intra-vlPAG injections of these drugs. DAMGO dose and pretreatment times were based upon Meyer et al 54 . In the α7 antagonist + PHA-543613 studies, MLA (90 pmol) or αBGT (1.5 pmol), were focally administered into the vlPAG 10 or 30 min prior to formalin injection, respectively, to allow for diffusion and binding to the receptors.…”

Section: Methodsmentioning

confidence: 99%

Nicotinic modulation of descending pain control circuitry

Umana

Daniele

Miller

et al. 2017

Pain

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Along with the well-known rewarding effects, activation of nicotinic acetylcholine receptors (nAChRs) can also relieve pain, and some nicotinic agonists have analgesic efficacy similar to opioids. A major target of analgesic drugs is the descending pain modulatory pathway, including the ventrolateral periaqueductal gray (vlPAG) and the rostral ventromedial medulla (RVM). Although activating nAChRs within this circuitry can be analgesic, little is known about the subunit composition and cellular effects of these receptors, particularly within the vlPAG. Using electrophysiology in brain slices from adult male rats, we examined nAChR effects on vlPAG neurons that project to the RVM. We found that 63% of PAG-RVM projection neurons expressed functional nAChRs, which were exclusively of the α7-subtype. Interestingly, the neurons that express α7 nAChRs were largely non-overlapping with those expressing µ-opioid receptors (MOR). As nAChRs are excitatory and MORs are inhibitory, these data suggest distinct roles for these neuronal classes in pain modulation. Along with direct excitation, we also found that presynaptic nAChRs enhanced GABAergic release preferentially onto neurons that lacked α7-nAChRs. In addition, presynaptic nAChRs enhanced glutamatergic inputs onto all PAG-RVM projection neuron classes to a similar extent. In behavioral testing, both systemic and intra-vlPAG administration of the α7 nAChR-selective agonist, PHA-543613, was antinociceptive in the formalin assay. Furthermore, intra-vlPAG α7 antagonist pretreatment blocked PHA-543613-induced antinociception via either administration method. Systemic administration of sub-maximal doses of the α7 agonist and morphine produced additive antinociceptive effects. Together, our findings indicate that the vlPAG is a key site of action for α7 nAChR-mediated antinociception.

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Analgesic tolerance to microinjection of the μ-opioid agonist DAMGO into the ventrolateral periaqueductal gray

Cited by 22 publications

References 38 publications

The Functional Antiopioid Action of the Ventrolateral Periaqueductal Gray Nociceptin/Orphanin FQ and Nociceptin Receptor System Underlies DAMGO Analgesic Tolerance

The Functional Antiopioid Action of the Ventrolateral Periaqueductal Gray Nociceptin/Orphanin FQ and Nociceptin Receptor System Underlies DAMGO Analgesic Tolerance

Extracellular Signal-Regulated Kinase 1/2 Activation Counteracts Morphine Tolerance in the Periaqueductal Gray of the Rat

Nicotinic modulation of descending pain control circuitry

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