Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray

Abstract

The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception.

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References 79

1. 1.

   Anseloni VC, Gold MS (2008 ) Inflammation-induced shift in the valence of spinal GABA-A receptor-mediated modulation of nociception in the adult rat. J Pain 9:732–738.

   Not in our library10.1016/j.jpain.2008.03.004

2. 2.

   Antal M, Odeh F (1998 ) The projections of the midbrain periaqueductal gray to serotonergic and noradrenergic nuclei of the pons and medulla oblongata in the rat. Eur J Neurosci 10:218–218.

   Not in our library10.1046/j.0953-816x.2001.01760.x

3. 3.

   Bandler R, Keay KA (1996 ) Columnar organization in the midbrain periaqueductal gray and the integration of emotional expression. Prog Brain Res 107:285–300.

   Not in our library10.1016/s0079-6123(08)61871-3

4. 4.

   Basbaum AI, Fields HL (1978 ) Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 4:451–462.

   Not in our library10.1002/ana.410040511

5. 5.

   Basbaum AI, Fields HL (1979 ) The origin of descending pathways in the dorsolateral funiculus of the spinal cord of the cat and rat: further studies on the anatomy of pain modulation. J Comp Neur 187:513–531.

   Not in our library10.1002/cne.901870304

6. 6.

   Baskin DS, Mehler WR, Hosobuchi Y, Richardson DE, Adams JE, Flitter MA (1986 ) Autopsy analysis of the safety, efficacy and cartography of electrical-stimulation of the central gray in humans. Brain Res 371:231–236.

   Not in our library10.1016/0006-8993(86)90358-6

7. 7.

   Behbehani MM (1995 ) Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol 46:575–605.

   Not in our library10.1016/0301-0082(95)00009-k

8. 8.

   Behbehani MM, Fields HL (1979 ) Evidence that an excitatory connection between the periaqueductal gray and nucleus raphe magnus mediates stimulation produced analgesia. Brain Res 170:85–93.

   Not in our library10.1016/0006-8993(79)90942-9

9. 9.

   Behbehani MM, Jiang MR, Chandler SD, Ennis M (1990 ) The effect of GABA and its antagonists on midbrain periaqueductal gray neurons in the rat. Pain 40:195–204.

   Not in our library10.1016/0304-3959(90)90070-t

10. 10.

    Beitz AJ, Mullett MA, Weiner LL (1983 ) The periaqueductal gray projections to the rat spinal trigeminal, raphe magnus, gigantocellular pars alpha and paragigantocellular nuclei arise from separate neurons. Brain Res 288:307–314.

    Not in our library10.1016/0006-8993(83)90108-7

11. 11.

    Bennett GJ, Mayer DJ (1979 ) Inhibition of spinal cord interneurons by narcotic microinjection and focal electrical stimulation in the periaqueductal central gray matter. Brain Res 172:243–257.

    Not in our library10.1016/0006-8993(79)90536-5

12. 12.

    Bowman BR, Kumar NN, Hassan SF, McMullan S, Goodchild AK (2013 ) Brain sources of inhibitory input to the rat rostral ventrolateral medulla. J Comp Neur 521:213–232.

    Not in our library10.1002/cne.23175

13. 13.

    Budai D, Fields HL (1998 ) Endogenous opioid peptides acting at mu-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons. J Neurophysiol 79:677–687.

    Not in our library10.1152/jn.1998.79.2.677

14. 14.

    Carstens E, Hartung M, Stelzer B, Zimmermann M (1990 ) Suppression of a hind-limb flexion withdrawal reflex by microinjection of glutamate or morphine into the periaqueductal gray in the rat. Pain 43:105–112.

    Not in our library10.1016/0304-3959(90)90055-i

15. 15.

    Carstens E, Stelzer B, Zimmermann M (1988 ) Microinjections of glutamate or morphine at coincident midbrain sites have different effects on nociceptive dorsal horn neurons in the rat. Neurosci Lett 95:185–191.

    Not in our library10.1016/0304-3940(88)90654-4

16. 16.

    Chieng B, Christie MD (1996 ) Local opioid withdrawal in rat single periaqueductal gray neurons in vitro. J Neurosci 16:7128–7136.

    Not in our library10.1523/jneurosci.16-22-07128.1996

17. 17.

    Depaulis A, Morgan MM, Liebeskind JC (1987 ) Gabaergic modulation of the analgesic effects of morphine microinjected in the ventral periaqueductal gray-matter of the rat. Brain Res 436:223–228.

    Not in our library10.1016/0006-8993(87)91665-9

18. 18.

    Duggan AW, Morton CR (1983 ) Periaqueductal grey stimulation: an association between selective inhibition of dorsal horn neurones and changes in peripheral circulation. Pain 15:237–248.

    Not in our library10.1016/0304-3959(83)90059-3

19. 19.

    Fields H (2004 ) State-dependent opioid control of pain. Nat Rev Neurosci 5:565–575.

    Not in our library10.1038/nrn1431

20. 20.

    Graeff FG, Silveira MC, Nogueira RL, Audi EA, Oliveira RM (1993 ) Role of the amygdala and periaqueductal gray in anxiety and panic. Behav Brain Res 58:123–131.

    Not in our library10.1016/0166-4328(93)90097-a

21. 21.

    Guo W, Robbins MT, Wei F, Zou S, Dubner R, Ren K (2006 ) Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation. J Neurosci 26:126–137.

    Not in our library10.1523/jneurosci.3686-05.2006

22. 22.

    Hahm ET, Kim Y, Lee JJ, Cho YW (2011 ) GABAergic synaptic response and its opioidergic modulation in periaqueductal gray neurons of rats with neuropathic pain. BMC Neurosci 12:41.

    Not in our library10.1186/1471-2202-12-41

23. 23.

    Hayes RL, Price DD, Ruda M, Dubner R (1979 ) Suppression of nociceptive responses in the primate by electrical stimulation of the brain or morphine administration: behavioral and electrophysiological comparisons. Brain Res 167:417–421.

    Not in our library10.1016/0006-8993(79)90838-2

24. 24.

    Heinricher MM, Cheng ZF, Fields HL (1987 ) Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray. J Neurosci 7:271–278.

    Not in our library10.1523/jneurosci.07-01-00271.1987

25. 25.

    Heinricher MM, Martenson ME, Neubert MJ (2004 ) Prostaglandin E2 in the midbrain periaqueductal gray produces hyperalgesia and activates pain-modulating circuitry in the rostral ventromedial medulla. Pain 110:419–426.

    Not in our library10.1016/j.pain.2004.04.026

26. 26.

    Heinricher MM, Tavares I, Leith JL, Lumb BM (2009 ) Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev 60:214–225.

    Not in our library10.1016/j.brainresrev.2008.12.009

27. 27.

    Ho YC, Cheng JK, Chiou LC (2013 ) Hypofunction of glutamatergic neurotransmission in the periaqueductal gray contributes to nerve-injury-induced neuropathic pain. J Neurosci 33:7825–7836.

    Not in our library10.1523/jneurosci.5583-12.2013

28. 28.

    Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005 ) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112.

    Not in our library10.1038/nature03658

29. 29.

    Holstege G (2014 ) The periaqueductal gray controls brainstem emotional motor systems including respiration. Prog Brain Res 209:379–405.

    Not in our library10.1016/b978-0-444-63274-6.00020-5

30. 30.

    Hosobuchi Y, Adams JE, Linchitz R (1977 ) Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. Science 197:183–186.

    Not in our library10.1126/science.301658

31. 31.

    Jacquet YF (1988 ) The Nmda receptor - central role in pain inhibition in rat periaqueductal gray. Eur J Pharmacol 154:271–276.

    Not in our library10.1016/0014-2999(88)90201-4

32. 32.

    Jensen TS, Yaksh TL (1989 ) Comparison of the antinociceptive effect of morphine and glutamate at coincidental sites in the periaqueductal gray and medial medulla in rats. Brain Res 476:1–9.

    Not in our library10.1016/0006-8993(89)91529-1

33. 33.

    Jones SL, Gebhart GF (1988 ) Inhibition of spinal nociceptive transmission from the midbrain, pons and medulla in the rat - activation of descending inhibition by morphine, glutamate and electrical-stimulation. Brain Res 460:281–296.

    Not in our library10.1016/0006-8993(88)90373-3

34. 34.

    Lau BK, Vaughan CW (2014 ) Descending modulation of pain: the GABA disinhibition hypothesis of analgesia. Curr Opin Neurobiol 29:159–164.

    Not in our library10.1016/j.conb.2014.07.010

35. 35.

    Liebeskind JC, Guilbaud G, Besson JM, Oliveras JL (1973 ) Analgesia from electrical stimulation of the periaqueductal gray matter in the cat: behavioral observations and inhibitory effects on spinal cord interneurons. Brain Res 50:441–446.

    Not in our library10.1016/0006-8993(73)90748-8

36. 36.

    Lü N, Han M, Yang ZL, Wang YQ, Wu GC, Zhang YQ (2010 ) Nociceptin/orphanin FQ in PAG modulates the release of amino acids, serotonin and norepinephrine in the rostral ventromedial medulla and spinal cord in rats. Pain 148:414–425.

    Not in our library10.1016/j.pain.2009.11.025

37. 37.

    Maione S, Bisogno T, de Novellis V, Palazzo E, Cristino L, Valenti M, Petrosino S, Guglielmotti V, Rossi F, Di Marzo V (2006 ) Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. J Pharmacol Exp Ther 316:969–982.

    Not in our library10.1124/jpet.105.093286

38. 38.

    Mantyh PW (1982 ) The midbrain periaqueductal gray in the rat, cat, and monkey: a Nissl, Weil, and Golgi analysis. J Comp Neur 204:349–363.

    Not in our library10.1002/cne.902040406

39. 39.

    Mayer DJ, Liebeskind JC (1974 ) Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioral analysis. Brain Res 68:73–93.

    Not in our library10.1016/0006-8993(74)90534-4

40. 40.

    McGaraughty S, Chu KL, Bitner RS, Martino B, El Kouhen R, Han P, Nikkel AL, Burgard EC, Faltynek CR, Jarvis MF (2003 ) Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM. J Neurophysiol 90:2702–2710.

    Not in our library10.1152/jn.00433.2003

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