, Volume 198, Issue 2, pp 271–278

Increased efficacy of μ-opioid agonist-induced antinociception by metabotropic glutamate receptor antagonists in C57BL/6 mice: comparison with (−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959)

  • Bradford D. Fischer
  • Laurence L. Miller
  • Fredrick E. Henry
  • Mitchell J. Picker
  • Linda A. Dykstra
Original Investigation



Recent experimental data suggest that metabotropic glutamate receptor (mGluR) antagonists with selectivity for mGluR1 and mGluR2/3 enhance morphine-induced antinociception.


The present study addressed the hypothesis that mGluR antagonists enhance opioid antinociception by increasing opioid efficacy.

Materials and methods

The antinociceptive effects of the partial μ-opioid receptor agonists buprenorphine and dezocine were first assessed in a hot-plate procedure under conditions of low (53°C) and high (56°C) stimulus intensity. Under conditions in which buprenorphine and dezocine produced submaximal antinociceptive effects, these drugs were assessed after pretreatment with the mGluR1 antagonist JNJ16259685, the mGluR5 antagonist MPEP, the mGluR2/3 antagonist LY341495, and for comparison, the N-methyl-D-aspartate (NMDA) receptor antagonist LY235959.


Buprenorphine (0.032–3.2 mg/kg) and dezocine (0.1–10 mg/kg) were fully efficacious at 53°C and produced submaximal antinociceptive effects at 56°C (i.e., their effects did not exceed 50% of the maximum possible effect). Pretreatment with JNJ16259685 (1.0–3.2 mg/kg), LY341495 (1.0–3.2 mg/kg), and LY235959 (0.32–1.0 mg/kg) enhanced the antinociceptive effects of buprenorphine and dezocine at 56°C, as revealed by significant increases in the peak effects of both drugs to ~100% maximum possible effect. In contrast, pretreatment with MPEP (1.0–3.2 mg/kg) did not modulate the antinociceptive effects of buprenorphine and dezocine.


These results suggest that, similar to the NMDA receptor antagonist LY235959, the mGluR1 antagonist JNJ16259685 and the mGluR2/3 antagonist LY341495 increase the antinociceptive efficacy of buprenorphine and dezocine.


Metabotropic Glutamate NMDA Opioid Efficacy Antinociception 


  1. Allen RM, Dykstra LA (2001) N-methyl-D-aspartate receptor antagonists potentiate the antinociceptive effects of morphine in squirrel monkeys. J Pharmacol Exp Ther 298:288–297PubMedGoogle Scholar
  2. Alvarez FJ, Villalba RM, Carr PA, Grandes P, Somohano PM (2000) Differential distribution of metabotropic glutamate receptors 1a, 1b, and 5 in the rat spinal cord. J Comp Neurol 422:464–487PubMedCrossRefGoogle Scholar
  3. Bond A, Lodge D (1995) Pharmacology of metabotropic glutamate receptor-mediated enhancement of responses to excitatory and inhibitory amino acids on rat spinal neurones in vivo. Neuropharmacology 34:1015–1023PubMedCrossRefGoogle Scholar
  4. Bossard AE, Guirimand F, Fletcher D, Gaude-Joindreau V, Chauvin M, Bouhassira D (2002) Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers. Pain 98:47–57PubMedCrossRefGoogle Scholar
  5. Cao CQ, Evans RH, Headley PM, Udvarhelyi PM (1995) A comparison of the effects of selective metabotropic glutamate receptor agonists on synaptically evoked whole cell currents of rat spinal ventral horn neurones in vitro. Br J Pharmacol 115:1469–1474PubMedGoogle Scholar
  6. Carlton SM, Hargett GL, Coggeshall RE (2001) Localization of metabotropic glutamate receptors 2/3 on primary afferent axons in the rat. Neuroscience 105:957–969PubMedCrossRefGoogle Scholar
  7. Cerne R, Randic M (1992) Modulation of AMPA and NMDA responses in rat spinal dorsal horn neurons by trans-1-aminocyclopentane-1,3-dicarboxylic acid. Neurosci Lett 144:180–184PubMedCrossRefGoogle Scholar
  8. Chen SL, Huang EY, Chow LH, Tao PL (2005) Dextromethorphan differentially affects opioid antinociception in rats. Br J Pharmacol 144:400–404PubMedCrossRefGoogle Scholar
  9. Dykstra LA (1990) Butorphanol, levallorphan, nalbuphine and nalorphine as antagonists in the squirrel monkey. J Pharmacol Exp Ther 254:245–252PubMedGoogle Scholar
  10. Fischer BD, Dykstra LA (2006) Interactions between an NMDA antagonist and low-efficacy opioid receptor agonists in assays of schedule-controlled responding and thermal nociception. J Pharmacol Exp Ther 318:1300–1306PubMedCrossRefGoogle Scholar
  11. Fischer BD, Zimmerman EI, Picker MJ, Dykstra LA (2008) Morphine in combination with metabotropic glutamate receptor antagonists on schedule-controlled responding and thermal nociception. J Pharmacol Exp Ther 324:732–739PubMedCrossRefGoogle Scholar
  12. Gharagozlou P, Demirci H, David Clark J, Lameh J (2003) Activity of opioid ligands in cells expressing cloned mu opioid receptors. BMC Pharmacol 3:1PubMedCrossRefGoogle Scholar
  13. Hoskins PJ, Hanks GW (1991) Opioid agonist–antagonist drugs in acute and chronic pain states. Drugs 41:326–344CrossRefGoogle Scholar
  14. Jia H, Rustioni A, Valtschanoff JG (1999) Metabotropic glutamate receptors in superficial laminae of the rat dorsal horn. J Comp Neurol 410:627–642PubMedCrossRefGoogle Scholar
  15. Jones CK, Eberle EL, Peters SC, Monn JA, Shannon HE (2005) Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing. Neuropharmacology 49:206–218PubMedCrossRefGoogle Scholar
  16. Kelso SR, Nelson TE, Leonard JP (1992) Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes. J Physiol 449:705–718PubMedGoogle Scholar
  17. King AE, Liu XH (1996) Dual action of metabotropic glutamate receptor agonists on neuronal excitability and synaptic transmission in spinal ventral horn neurons in vitro. Neuropharmacology 35:1673–1680PubMedCrossRefGoogle Scholar
  18. Kozela E, Pilc A, Popik P (2003) Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice. Psychopharmacology 165:245–251PubMedGoogle Scholar
  19. Morgan D, Cook CD, Smith MA, Picker MJ (1999) An examination of the interactions between the antinociceptive effects of morphine and various μ-opioids: the role of intrinsic efficacy and stimulus intensity. Anesth Analg 88:407–413PubMedCrossRefGoogle Scholar
  20. Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J, Weinberg RJ, Worley PF, Sheng M (1999) Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23:569–582PubMedCrossRefGoogle Scholar
  21. Nemmani KV, Grisel JE, Stowe JR, Smith-Carliss R, Mogil JS (2004) Modulation of morphine analgesia by site-specific N-methyl-D-aspartate receptor antagonists: dependence on sex, site of antagonism, morphine dose, and time. Pain 109:274–283PubMedCrossRefGoogle Scholar
  22. Preston KL, Jasinski DR (1991) Abuse liability studies of opioid agonist–antagonists in humans. Drug Alcohol Depend 28:49–82PubMedCrossRefGoogle Scholar
  23. Skeberdis VA, Lan J, Opitz T, Zheng X, Bennett MV, Zukin RS (2001) mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C. Neuropharmacology 40:856–865PubMedCrossRefGoogle Scholar
  24. Toll L (1995) Intact cell binding and the relation to opioid activities in SH-SY5Y cells. J Pharmacol Exp Ther 273:721–727PubMedGoogle Scholar
  25. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23:583–592PubMedCrossRefGoogle Scholar
  26. Walker EA, Butelman ER, DeCosta BR, Woods JH (1993) Opioid thermal antinociception in rhesus monkeys: receptor mechanisms and temperature dependency. J Pharmacol Exp Ther 267:280–286PubMedGoogle Scholar
  27. Wessinger WD (1986) Approaches to the study of drug interactions in behavioral pharmacology. Neurosci Biobehav Rev 10:103–113PubMedCrossRefGoogle Scholar
  28. Yoon MH, Choi J, Bae HB, Kim SJ, Chung ST, Jeong SW, Chung SS, Yoo KY, Jeong CY (2006) Antinociceptive effects and synergistic interaction with morphine of intrathecal metabotropic glutamate receptor 2/3 antagonist in the formalin test of rats. Neurosci Lett 394:222–226PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Bradford D. Fischer
    • 1
  • Laurence L. Miller
    • 1
  • Fredrick E. Henry
    • 1
  • Mitchell J. Picker
    • 1
  • Linda A. Dykstra
    • 1
  1. 1.Department of PsychologyUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations