Endogenous opioids acting at a medullary μ-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray

Roychowdhury, Swagata; Fields, Howard L.

doi:10.1016/0306-4522(96)00180-7

Cited by 83 publications

(31 citation statements)

References 40 publications

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“…Neither CTAP nor NTB altered PWL when microinjected in the RVM of saline-treated rats, suggesting that RVM neurons do not normally receive tonically active opioid inputs (Kiefel et al, 1993;Roychowdhury and Fields, 1996;Thorat and Hammond, 1997;Hirakawa et al, 1999). Yet, in CFA-treated rats, microinjection of NTB in the RVM decreased PWL in both the ipsilateral and contralateral hindpaws.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Endogenous Enkephalins to the Enhanced Analgesic Effects of Supraspinal μ Opioid Receptor Agonists after Inflammatory Injury

Hurley

Hammond

2001

J. Neurosci.

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This study examined a mechanism responsible for the enhanced antihyperalgesic and antinociceptive effects of the opioid receptor agonist (ORA) [D-Ala 2 , NMePhe 4 , Gly 5 -ol]enkephalin (DAMGO) microinjected in the rostroventromedial medulla (RVM) of rats with inflammatory injury induced by injection of complete Freund's adjuvant (CFA) in one hindpaw. In rats injected with CFA 4 hr earlier, microinjection of the opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH 2 (CTAP) in the RVM antagonized both the marginal enhancement of the potency of DAMGO and its antinociceptive effect. The ␦ opioid receptor antagonist naltriben (NTB) was without effect. In rats injected with CFA 2 weeks earlier, CTAP antagonized the effects of DAMGO to a lesser extent. However, NTB completely prevented the enhancement of the potency of DAMGO, whereas it did not antagonize DAMGO's antinociceptive effects. Microinjection of NTB alone, but not CTAP in the RVM of CFA-treated rats, enhanced the hyperalgesia present in the ipsilateral hindpaw and induced hyperalgesia in the contralateral, uninjured hindpaw. These results suggest that persistent inflammatory injury increased the release in the RVM of opioid peptides with preferential affinity for the ␦ opioid receptor, which can interact in a synergistic or additive manner with an exogenously administered opioid receptor agonist. Indeed, the levels of [Met 5 ]enkephalin and [Leu 5 ]enkephalin were increased in the RVM and in other brainstem nuclei in CFAtreated rats. This increase most likely presents a compensatory neuronal response of the CNS of the injured animal to mitigate the full expression of inflammatory pain and to enhance the antinociceptive and antihyperalgesic effects of exogenously administered opioid receptor analgesics. Key words: opioid receptor; ␦ opioid receptor; antinociception; complete Freund's adjuvant; hyperalgesia; nucleus raphe magnusPeripheral inflammatory injury alters the pharmacology and physiology of primary afferent fibers that convey tactile and nociceptive information (Noguchi et al., 1988;Schaible and Schmidt, 1988;Donaldson et al., 1992;Ji et al., 1995;Leslie et al., 1995;Neumann et al., 1996;Tanaka et al., 1998), as well as the pharmacology and physiology of the dorsal horn neurons on which they synapse (Hylden et al., 1989;Noguchi et al., 1989;Weihe et al., 1989;McCarson and Krause, 1994;Goff et al., 1998). More recently, peripheral inflammation has been recognized to also affect the efferent pain modulatory pathways. For example, persistent inflammatory injury can enhance either the inhibition or facilitation of spinal nociceptive transmission by medullary or pontine neurons (Schaible et al., 1991;Herrero and Cervero, 1996;Ren and Dubner, 1996;Tsuruoka and Willis, 1996;Urban et al., 1996Urban et al., , 1999Kauppila et al., 1998;Wei et al., 1998Wei et al., , 1999MacArthur et al., 1999;Terayama et al., 2000). Alterations in the activity of supraspinal neurons were inferred in most of these studies from lesion-induced changes in response...

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Section: Discussionmentioning

confidence: 99%

Contribution of Endogenous Enkephalins to the Enhanced Analgesic Effects of Supraspinal μ Opioid Receptor Agonists after Inflammatory Injury

Hurley

Hammond

2001

J. Neurosci.

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“…Opioid antagonists in the RVM also appear to be responsible for other antinociceptive actions in the vlPAG since antinociception elicited by the GABA A receptor antagonist, bicuculline, in the vlPAG is significantly reduced by RVM pretreatment with either general (naltrexone) or Ì-selective (CTOP) opioid antagonists [72]. Importantly, these antagonists were ineffective in reducing bicuculline antinociception when they were injected into misplaced medullary placements.…”

Section: Opioid Agonists In the Vlpag And Opioid Antagonists In The Rvmmentioning

confidence: 99%

Supraspinal Circuitry Mediating Opioid Antinociception: Antagonist and Synergy Studies in Multiple Sites

Bodnar¹

2000

J Biomed Sci

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Supraspinal opioid antinociception is mediated by sensitive brain sites capable of supporting this response following microinjection of opioid agonists. These sites include the ventrolateral periaqueductal gray (vIPAG), the rostral ventromedial medulla (RVM), the locus coeruleus and the amygdala. Each of these sites comprise an interconnected anatomical and physiologically relevant system mediating antinociceptive responses through regional interactions. Such interactions have been identified using two pharmacological approaches: (1) the ability of selective antagonists delivered to one site to block antinociception elicited by opioid agonists in a second site, and (2) the presence of synergistic antinociceptive interactions following simultaneous administration of subthreshold doses of opioid agonists into pairs of sites. Thus, the RVM has essential serotonergic, opioid, cholinergic and NMDA synapses that are necessary for the full expression of morphine antinociception elicited from the vIPAG, and the vIPAG has essential opioid synapses that are necessary for the full expression of opioid antinociception elicited from the amygdala. Further, the vIPAG, RVM, locus coeruleus and amygdala interact with each other in synergistically supporting opioid antinociception.

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“…The antinociceptive responses to the small amounts of BIC (20 pmol in 50 nl) microinjected into the vlPAG have a rapid onset and were transient and reversible, allowing subsequent testing with other substances (21). The responses of WDR neurons in the TCC to electrical stimulation of the MMA were monitored before and after microinjecting CGRP, CGRP-(8-37), olcegepant, or saline vehicle control into the vlPAG.…”

Section: Experimental Protocolmentioning

confidence: 99%

Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons

et al. 2015

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Endogenous opioids acting at a medullary μ-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray

Cited by 83 publications

References 40 publications

Contribution of Endogenous Enkephalins to the Enhanced Analgesic Effects of Supraspinal μ Opioid Receptor Agonists after Inflammatory Injury

Contribution of Endogenous Enkephalins to the Enhanced Analgesic Effects of Supraspinal μ Opioid Receptor Agonists after Inflammatory Injury

Supraspinal Circuitry Mediating Opioid Antinociception: Antagonist and Synergy Studies in Multiple Sites

Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons

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