Elsevier

Neuroscience

Volume 118, Issue 3, 25 May 2003, Pages 789-796
Neuroscience

Research paper
Spinal pharmacology of antinociception produced by microinjection of μ or δ opioid receptor agonists in the ventromedial medulla of the rat

https://doi.org/10.1016/S0306-4522(03)00041-1Get rights and content

Abstract

This study examined the role of spinal GABAergic, serotoninergic and α2 adrenergic receptors in the antinociception produced by the microinjection of equi-antinociceptive doses of selective opioid receptor agonists in the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars α (NGCpα) of the rat. Rats were pretreated with intrathecal administration of either the GABAA receptor antagonist bicuculline, the GABAB receptor antagonist CGP35348, the serotonin1/2 receptor antagonist methysergide, the α2 adrenergic receptor antagonist yohimbine or saline. Ten minutes later, either the δ1 opioid receptor agonist [D-Pen2,5]enkephalin (DPDPE), δ2 opioid receptor agonist [D-Ala2,Glu4]deltorphin (DELT) or μ opioid receptor agonist [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO) was microinjected into the NRM, NGCpα or sites in the medulla outside these two regions. The increase in tail-flick latency produced by microinjection of DPDPE into the NRM or NGCpα was antagonized by intrathecal pretreatment with either methysergide or yohimbine. Intrathecal pretreatment with CGP35348 antagonized the antinociception produced by microinjection of DPDPE in the NRM, whereas bicuculline antagonized the antinociception produced by microinjection of DPDPE in the NGCpα. The increase in tail-flick latency produced by microinjection of DELT into the NGCpα, but not the NRM was antagonized by intrathecal pretreatment with yohimbine or CGP35348. Intrathecal pretreatment with methysergide or bicuculline did not antagonize the antinociception produced by microinjection of DELT into either the NRM or the NGCpα. The increase in tail-flick latency produced by microinjection of DAMGO in the NRM was antagonized by intrathecal pretreatment with methysergide or CGP35348, but not by bicuculline or yohimbine. Taken together, these results support the hypothesis that the antinociception produced by activation of δ1, δ2 or μ opioid receptors in the rostral ventromedial medulla is mediated by different neural substrates.

Section snippets

Abbreviations used in the figures

    dcn

    dorsal cochlear nucleus

    icp

    inferior cerebellar peduncle

    ngc

    nucleus reticularis gigantocellularis

    nV

    spinal trigeminal nucleus

    nVII

    facial motor nucleus

    P

    pyramid

    tb

    trapezoid body

    7g

    genu of the seventh cranial nerve

    7t

    tract of the seventh cranial nerve

Experimental procedures

These experiments were approved by the Institutional Animal Care and Use Committee of the University of Chicago. All procedures were conducted in accordance with the “Guide for Care and Use of Laboratory Animals” published by the National Institutes of Health and the ethical guidelines of the International Association for the Study of Pain. Every effort was made to minimize animal suffering and to limit the number of animals used.

Microinjection sites

Histological analysis revealed a comparable distribution of injection sites throughout the rostral-caudal extent of the NRM and NGCpα in each treatment group. Some sites that impinged on the rostral edge of the nucleus reticularis paragigantocellularis lateralis were included in the NGCpα for purposes of data analysis. Fig. 1 illustrates the distribution of injection sites for a representative treatment group. Microinjection of DPDPE, DELT or DAMGO at sites outside these two nuclei, such as the

Activation of δ1, δ2 or μ opioid receptors in the rvm produces antinociception

The NRM and NGCpα are often considered to be a functional unit because electrical or chemical activation of neurons in either region can produce similar antinociceptive effects. However, substantial pharmacological and anatomical evidence indicates that the afferent and efferent connections of these two nuclei and their neurotransmitter content are not identical. For example, the antinociception produced by electrical stimulation or microinjection of L-glutamate in the NRM or NGCpα can be

Acknowledgements

This study was supported by U.S. Public Health Service grants DA06736 (D.L.H.) and DA05784 (R.W.H.) from the National Institute on Drug Abuse. We thank Sanjay N. Thorat, Kenneth Park, and Laura Skrocki for their assistance with aspects of this work.

References (48)

  • T.S. Jensen et al.

    Examination of spinal monoamine receptors through which brainstem opiate-sensitive systems act in the rat

    Brain Res

    (1986)
  • T.S. Jensen et al.

    Comparison of the antinociceptive action of mu and delta opioid receptor ligands in the periaqueductal gray matter, medial and paramedial ventral medulla in the rat as studied by the microinjection technique

    Brain Res

    (1986)
  • M.K. McGowan et al.

    Antinociception produced by microinjection of L-glutamate into the ventromedial medulla of the ratmediation by spinal GABAA receptors

    Brain Res

    (1993)
  • M.K. McGowan et al.

    Intrathecal GABAB antagonists attenuate the antinociception produced by microinjection of L-glutamate into the ventromedial medulla of the rat

    Brain Res

    (1993)
  • M.J. Millan

    Descending control of pain

    Prog Neurobiol

    (2002)
  • M.H. Ossipov et al.

    Characterization of supraspinal antinociceptive actions of opioid delta agonists in the rat

    Pain

    (1995)
  • F. Porreca et al.

    Chronic pain and medullary descending facilitation

    Trends Neurosci

    (2002)
  • J.J. Rady et al.

    Spinal GABA receptors mediate brain delta opioid analgesia in Swiss Webster mice

    Pharmacol Biochem Behav

    (1995)
  • J.J. Rady et al.

    Supraspinal delta2 opioid agonist analgesia in Swiss-Webster mice involves spinal GABAA receptors

    Pharmacol Biochem Behav

    (1996)
  • G.C. Rossi et al.

    Mu and delta opioid synergy between the periaqueductal gray and the rostro-ventral medulla

    Brain Res

    (1994)
  • M. Satoh et al.

    Analgesia produced by microinjection of L-glutamate into the rostral ventromedial bulbar nuclei of the rat and its inhibition by intrathecal alpha-adrenergic blocking agents

    Brain Res

    (1983)
  • C. Schmauss et al.

    Pharmacological antagonism of the antinociceptive effects of serotonin in the rat spinal cord

    Eur J Pharmacol

    (1983)
  • H.-W. Suh et al.

    Effects of GABA receptor antagonists injected spinally on antinociception induced by opioids administered supraspinally in mice

    Eur J Pharmacol

    (1996)
  • S.A. Tershner et al.

    Brainstem pain modulating circuitry is sexually dimorphic with respect to mu and kappa opioid receptor function

    Pain

    (2000)
  • Cited by (42)

    • Abdominal Pain

      2022, Comprehensive Pharmacology
    • Changes in response properties of rostral ventromedial medulla neurons during prolonged inflammation: Modulation by neurokinin-1 receptors

      2012, Neuroscience
      Citation Excerpt :

      The RVM, which includes the Nucleus Raphe Magnus, the Nucleus Reticularis Gigantocellularis, the Nucleus Gigantocellularis pars alpha, and the Nucleus Paragigantocellularis lateralis, plays an important role in spinal nociceptive processing as a relay structure of descending modulation (Basbaum and Fields, 1984; Fields et al., 1991; Watkins et al., 1998; Urban and Gebhart, 1999; Urban et al., 1999a,b; Millan, 2002), including facilitation of nociceptive transmission and the development of hyperalgesia. Studies have shown that the RVM contributes to hyperalgesia produced by inflammation (Montagne-Clavel and Oliveras, 1994; Watkins et al., 1994; Wiertelak et al., 1994; Hurley and Hammond, 2000; Hurley et al., 2003; Pacharinsak et al., 2008; Hamity et al., 2010), nerve injury (Pertovaara et al., 1996; Burgess et al., 2002), chronic opioid administration (Kaplan and Fields, 1991; Meng and Harasawa, 2007), cancer (Donovan-Rodriguez et al., 2006), and visceral pain (Coutinho et al., 1998; Zhuo and Gebhart, 2002; Zhuo et al., 2002). Neurons in the RVM are classified physiologically as ON, OFF, NEUTRAL, and serotonergic cells.

    • High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups

      2011, Brain Research
      Citation Excerpt :

      However, since our autoradiogram-based ISH method lacks cellular resolution, we cannot be sure whether or not the c-fos differences are confined to 5-HTergic neurons. Numerous studies have characterized non-5-HTergic neurons within the raphe that powerfully modulate 5-HTergic neurons, such as GABA-mediated inhibition of cell firing and transmitter release (Hurley et al., 2003; Melander et al., 1986). We are currently refining a dual-label ISH methodology for quantifying c-fos within neurochemically defined raphe neurons, as well as with laser-capture microdissection coupled with high-throughput gene expression assays (Kerman et al., 2006a).

    • Rostral ventromedial medulla μ, but not κ, opioid receptors are involved in electroacupuncture anti-hyperalgesia in an inflammatory pain rat model

      2011, Brain Research
      Citation Excerpt :

      It has been demonstrated that EA inhibits hyperalgesia by activating serotonergic RVM neurons that project to the spinal cord (Li et al., 2007). In another study, an intra-RVM infusion of DAMGO produced an increase of tail-flick latency that was blocked by intrathecal pretreatment with methysergide, a serotonin receptor antagonist (Hurley et al., 2003). These findings suggest that an EA-activated opioid system in the RVM may inhibit pain through a descending serotonergic system in the spinal cord.

    View all citing articles on Scopus
    View full text