Elsevier

Brain Research

Volume 558, Issue 2, 6 September 1991, Pages 224-230
Brain Research

Synergistic analgesic interactions between the periaqueductal gray and the locus coeruleus

https://doi.org/10.1016/0006-8993(91)90772-NGet rights and content

Abstract

Opiates modulate pain perception at a number of different levels within the central nervous system and the importance of synergistic spinal and supraspinal influences have been well documented. In the present study we demostrate synergistic interactions between the periaqueductal gray and locus coeruleus. Administered either systemically or intracerebroventricularly (i.c.v.), ethylketocyclazonine elicits a potent naloxonazine-sensitive analgesia, indicating aμ1 action.μ1 Receptors also play a major role in opioid analgesic mechanisms in the periaqueductal gray and the locus coeruleus. However, microinjection of EKC into either the periaqueductal gray or locus coeruleus failed to elicit an analgesic response at any dose tested (0.1–20 μg) and, in additional studies, antagonized the analgesic actions of coadministered morphine or [D-Ser2,Leu5]enkephalin-Thr6 (DSLET). However, the simultaneous administration of EKC into both the periaqueductal gray (10 μg) and the locus coeruleus (10 μg; total combined dose 20 μg) produced a potent naloxonazine-sensitive analgesia greater than that observed with 50 μg i.c.v. These results suggest that EKC is a partialμ1 agonist which lacks the efficacy to elicit analgesia when microinjected into either of the two brain regions alone. However, when exposed to several regions at once, either through simultaneous microinjections into the periaqueductal gray and locus coeruleus or by injection into the ventricle, EKC is a potentμ1 analgesic. These results point out the existence of synergistic supraspinal interactions between the periaqueductal gray and the locus coeruleus, similar to the spinal/supraspinal interactions observed previously.

Reference (65)

  • LingG.S.F. et al.

    Naloxonazine actions in vivo

    Eur. J. Pharmacol.

    (1986)
  • LingG.S.F. et al.

    Spinal and supraspinal analgesia in the mouse: the role of subpopulations of opioid binding sites

    Brain Research

    (1983)
  • MathiasenJ.R. et al.

    [d-Pen2,l-Pen5]enkephalin induced analgesia in the jimpy mouse: in vivo evidence for delta receptor mediated analgesia

    Eur. J. Pharmacol.

    (1987)
  • PaulD. et al.

    Different mu receptor subtypes mediate spinal and supraspinal analgesia in mice

    Eur. J. Pharmacol.

    (1989)
  • PertA. et al.

    Sites of morphine induced analgesia in the primate brain: relation to pain pathways

    Brain Research

    (1974)
  • RothmanR.B. et al.

    Autoradiographic evidence for two classes of mu opioid binding sites in rat brain using [125I]FK33824

    Peptides

    (1987)
  • SatohM. et al.

    Comparison of analgesic potencies of mu, delta and kappa agonists locally applied to various CNS region relevant to analgesia in rats

    Life Sci.

    (1983)
  • SegalM. et al.

    Analgesia produced by electrical stimulation of catecholamine nuclei in the rat brain

    Brain Research

    (1977)
  • SharpeL.G. et al.

    Analgesia or hyperreactivity produced by intracranial microinjections of morphine into the periaqueductal gray matter

    Behav. Biol.

    (1974)
  • SheldonR.J. et al.

    U-50,488H differentially antagonizes the bladder effects of mu agonists at spinal sites

    Eur. J. Pharmacol.

    (1988)
  • SmithD.J. et al.

    The μ receptor is responsible for descending pain inhibition originating in the periaqueductal gray region of the rat brain

    Eur. J. Pharmacol.

    (1988)
  • TungA.S. et al.

    In vivo evidence of multiple opiate receptors mediating analgesia in the raa spinal cord

    Brain Research

    (1982)
  • WoodP.L. et al.

    Spinal analgesia: comparison of the mu agonist morphine and the kappa agonist ethylketocyclazocine

    Life Sci.

    (1981)
  • YakshT.L. et al.

    Systematic examination in the rat of brain sites sensitive to the direct application of morphine: observation of differential effects within the periaqueductal gray

    Brain Research

    (1976)
  • YakshT.L. et al.

    Peripheral and central substrates involved in the rostrad transmission of nociceptive information

    Pain

    (1982)
  • ClarkJ.A. et al.

    Opiate binding in calf thalamic membranes: a selectiveμ1 binding assay

    Mol. Pharmacol.

    (1988)
  • ClarkJ.A. et al.

    Kappa receptor multiplicity: evidence for two U50,488H-sensitiveκ1 subtypes and a novelκ3 subtype

    J. Pharmacol. Exp. Ther.

    (1989)
  • D'AmourF.E. et al.

    A method for determining loss of pain sensation

    J. Pharmacol. Exp. Ther.

    (1941)
  • FangF.G. et al.

    Action at the μ receptor is sufficient to explain the supraspinal analgesic effect of opiates

    J. Pharmacol. Exp. Ther.

    (1986)
  • FredericksonR.C.A. et al.

    Metkephamid, a systemically active analog of methionine enkephalin with potent opioid deltareceptor activity

    Science

    (1981)
  • FriedmanH.J. et al.

    Dynorphin: a possible modulatory peptide on morphine or betaendorphin analgesia in the mouse

    Eur. J. Pharmacol.

    (1984)
  • GalliganJ.J. et al.

    Cerebral delta opioid receptors mediate analgesia but not the intestinal motility effects of intracerebroventricularly administered opioids

    J. Pharmacol. Exp. Ther.

    (1984)
  • Cited by (31)

    • Naloxone-induced analgesia mediated by central kappa opioid system in chronic inflammatory pain

      2021, Brain Research
      Citation Excerpt :

      However, the supraspinal KOR system contributes to the production of affective pain rather than analgesia (Knoll et al., 2007). The prototypical kappa opioid agonist, ethylketocyclazocine, only produce analgesia following co-administration into the periaqueductal gray and the locus coeruleus that was blocked by the mu1-selective antagonist, naloxonazine (Bodnar et al., 1991). The KOR system is also known to be facilitated within the limbic system in chronic pain, resulting in suppression of the morphine-induced rewarding effect in rats (Narita et al., 2005).

    • Opioid selective antinociception following microinjection into he periaqueductal gray of the rat

      2014, Journal of Pain
      Citation Excerpt :

      Microinjection of morphine, fentanyl, oxycodone, DAMGO, dermorphin, ß-endorphin, morphine-6ß-glucuronide, and [d-Ser2,Leu5]enkephalin-Thr6 into the PAG produces clear antinociceptive effects,5,7,27,42,50 whereas microinjection of methadone or buprenorphine has no effect. Likewise, antinociception does not occur following microinjection of the delta or kappa opioid receptor agonist deltorphin or ethylketocyclazocine into the PAG.6,32 These data demonstrate that even though opioids produce antinociception by binding to MOPrs, differences in MOPrs determine whether opioid binding is sufficient to produce antinociception.

    View all citing articles on Scopus
    View full text