Cellular Physiology of Pain

This group was established at PMRI in 2000. The main focus of our research group is the examination of the cellular mechanisms of pain transmission within the central nervous system and of novel analgesic agents, particularly cannabinoids. This work is carried out largely by using in vitro patch clamp recording techniques to examine neurotransmitter actions on synaptic transmission in the spinal cord and brainstem. The in vitro patch clamping is often used in combination with anatomical tract tracing and immunohistochemical techniques to aid identification of pain pathways.

This other focus of our group is the examination of chronic pain states, particularly inflammatory pain and nerve injury induced neuropathic pain. In addition, our group is increasingly using behavioural techniques to examine the analgesic actions of novel compounds, particularly cannabinoids and modulators of the endocannabinoid transmitter system in chronic inflammatory and neuropathic pain models. This behavioural work is complements the in vitro studies which are examining cellular/molecular targets.

Achievements

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  • Discovery of cannabinoid actions in brainstem pain control pathways which provide a cellular substrate for the analgesic activity of cannabinoids.
  • Discovery of mechanisms of central integration of cold sensation in the spinal cord dorsal horn and the involvement of TRP related ion channels.
  • Discovery of G-protein coupled receptor responses to glutamate in brainstem pain control pathways and their interaction with endogenously released cannabinoids.
  • Discovery of cellular actions of opioids in anatomically identified brainstem pain control pathways (in collaboration with M Wessendorf, M Christie).
  • Discovery of the cellular actions of a number of pain related neuropeptides in brainstem pain control pathways.
  • Discovery of VR1-mediated stimulation of glutamatergic synaptic transmission by capsaicin in the locus coeruleus, the first direct demonstration of synaptic effects of VR1 activation outside the spinal cord (in collaboration with M Connor)
  • We are currently examining nociceptive mechanisms and analgesic drug actions in the brainstem, plus their alteration in chronic pain states. In particular we will be examining the role of the endogenous cannabinoid transmitter systems and how this might be manipulated to provide analgesic therapies.

Main projects

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  • Cellular actions of endogenously released cannabinoids
  • Cellular actions of cannabinoids in spinal cord pain pathways
  • New drugs for treating pain.

Group Leader

Dr Chris Vaughan

Staff

• Chris Vaughan PhD, Principal Hospital Scientist (Royal North Shore Hospital), Clinical Senior Lecturer (Uni. Sydney)
• Paul Wrigley, MBBS MM PhD, Pain Medicine Senior Staff Specialist, Clinical Senior Lecturer, Research Fellow & Supervisor of Training (Faculty of Pain Medicine)
• Geoff Drew PhD, NH&MRC CJ Martins Postdoctoral Fellow
• Vanessa Mitchell MSc, Research Assistant
• Benjamin Lau BSc (Hons), PhD Student
• Michelle Buttfield BM MRCP, PhD Student
• Angelo Jayamanne, BSc (Hons), PhD Student
• Karen Lam, BSc, Honours Student

Publications

Peer reviewed articles:

• Drew GM, Mitchell VA & Vaughan CW (2008) Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling. J Neurosci, 28(4):808-15.
• Vuong LAQ, Mitchell VA & Vaughan CW (2008) Actions of N-arachidonyl-glycine in a rat neuropathic pain model. Neuropharmacology 54(1):189-93
• Succar R, Mitchell VA & Vaughan CW (2007) Actions of N-arachidonyl-glycine in a rat inflammatory pain model. Molecular Pain, 3:24.
• Mitchell VA, Greenwood R, Jayamanne A & Vaughan CW (2007) Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models. Clinical and Experimental Pharmacology and Physiology, 34 (11):1186-90.
• Ekberg J, Jayamanne A, Vaughan CW, Aslan S, Thomas L, Mouldt J, Drinkwater R, Baker MD, Abrahamsen B, Wood JN, Adams DJ, Christie MJ,  Lewis RJ (2006) µO-conotoxin MrVIB selectively blocks Na(v)1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proc. Natl. Acad. Sci. USA, 103: 17030-17035.
• Jayamanne A, Greenwood R, Mitchell VA, Aslan S, Piomelli D & Vaughan CW (2006) Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. British Journal of Pharmacology, 147(3): 281-288.
• Mitchell VA, Aslan S, Safaei R & Vaughan CW (2005) Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neuroscience Letters, 382: 231 - 235.
• Drew GM, Mitchell VA, Vaughan CW (2005) Postsynaptic actions of substance P on rat periaqueductal grey neurons in vitro. Neuropharmacology, 49: 587-595.
• Marinelli S, Connor M, Schnell SA, Christie MJ, Wessendorf MW & Vaughan CW (2005) d-Opioid receptor-mediated actions on rostral ventromedial medulla neurons. Neuroscience, 132:239-244.
• Bagley EE, Gerke MB, Vaughan CW, Hack SP & Christie MJ (2005) GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal. Neuron, 45:433 – 445.
• Marinelli S, Schell SA, Hack SP, Christie MJ, Wessendorf MW & Vaughan CW (2004). Serotonergic and non-serotonergic dorsal raphe neurons are pharmacologically and electrophysiologically heterogeneous. Journal of Neurophysiology, 92(6): 3532-3537.
• Drew GM & Vaughan CW (2004). Multiple metabotropic glutamate receptor subtypes modulate GABAergic neurotransmission in rat periaqueductal grey neurons in vitro. Neuropharmacology, 46(7):927-934.
• Connor M, Bagley EE, Mitchell VA, Ingram SL, Christie MJ, Humphrey PPA & Vaughan CW (2004). Cellular actions of somatostatin on rat periaqueductal grey neurons in vitro. British Journal of Pharmacology, 142: 1273-1280.
• Gavioli EC, Vaughan CW, Marzola G, Guerrini R, Mitchell VA, Zucchini S, De Lima TCM, Rae GA, Salvadori S, Regoli D, and Calo’ G (2004) Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidences in rats and mice. Naunyn-Schmiedeberg’s Archives of Pharmacology, 369 : 547-553.
• Mitchell VA, Christie MJ & Vaughan CW (2003) Developmental changes in the a-adrenergic responses of rat periaqueductal grey neurons. Neuroreport, 14(12): 1637-1639.
  
• Hack SP, Vaughan CW & Christie MJ (2003) Modulation of GABA release during morphine withdrawal in midbrain neurons in vitro. Neuropharmacology, 45(5): 575-584.
• Vaughan CW, Bagley EE, Drew GM, Schuller A, Pintar JE, Hack SP & Christie MJ (2003) Cellular actions of opioids on periaqueductal grey neurons from C56B16/J mice and mutant mice lacking MOR-1. British Journal of Pharmacology, 139: 362-367.
• Jennings EA, Vaughan CW, Roberts LA & Christie MJ (2003). The actions of anandamide on rat superficial medullary dorsal horn neurons, in vitro. Journal of Physiology, 548: 121-129.
• Marinelli S, Vaughan CW, Schnell SA, Wessendorf MW & Christie MJ (2002) Rostral ventromedial medulla neurons that project to the spinal cord express multiple opioid receptor phenotypes. Journal of Neuroscience, 22:10847 - 10855.
• Marinelli S, Vaughan CW, Christie MJ & Connor M (2002) Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro. Journal of Physiology, 543: 531-540.
• Jennings EA, Vaughan CW & Christie MJ (2001) Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. Journal of Physiology, 534:805-812.
• Vaughan CW, Connor M, Jennings EA, Marinelli S, Allen RG & Christie MJ (2001) Actions of nociceptin/orphan FQ and other prepronociceptin products on rostral ventromedial medulla neurons in vitro Journal of Physiology, 534: 849-859.
   
  Reviews & Book Chapters:
• Vaughan CW & Drew GM (2007) Cellular actions of cannabinoids and opioids in descending analgesic systems (2007). In: Neurotransmitters in the Antinociceptive Descending Pathways. S Maione & V Di Marzo (Eds.) Research Signpost, Kerala (in press).
• Wessendorf MW, Vaughan CW & Vanegas H (2006) Rethinking the PAG and RVM: Supraspinal modulation of nociception by opioids and non-opioids. In: Proceedings of the 11th World Congress on Pain. H Flor, E Kalso, Dostrovsky JO (Eds.), IASP Press, Seattle, pages 311-320.
  
• Vaughan CW (2006) Stressed-out endogenous cannabinoids relieve pain. Trends in Pharmacological Sciences 27: 69-71.
  
• Vaughan CW & Christie MJ (2005) Retrograde endocannabinoid signalling. In: Handbook of Experimental Pharmacology, Cannabinoids (Vol. 168). R Pertwee (Ed.), Springer Verlag, Berlin, pages 367-383.
• Connor M & Vaughan CW (2005) Humanizing mice: catching up with elusive B1 receptors. British Journal of Pharmacology, Invited review, 144:885-886.
• Vaughan CW & Christie MJ (2004) Mechanismen der cannabinoidanalgesie. In: Cannabis und Cannabinoide - Pharmakologie, Toxikologie und therapeutisches Potential. F Grotenhermen (Ed.), Verlag Vans Huber, Bern, 2nd edition, pp. 115-125.
• Vaughan CW & Connor M (2003) In search of a role for the morphine metabolite morphine-3-glucuronide. Anesthesia & Analgesia, 97(2): 311-312.
• Vaughan CW & Christie MJ (2002) Mechanisms of cannabinoid analgesia. In: Cannabis and cannabinoids: pharmacology, toxicology and therapeutic potential. F Grotenhermen & E Russo (Eds.), Haworth Press, New York, pp. 89-99.
• Vaughan CW & Christie MJ (2001) Mechanismen der cannabinoidanalgesie. In: Cannabis und Cannabinoide - Pharmakologie, Toxikologie und therapeutisches Potential. F Grotenhermen (Ed.), Verlag Vans Huber, Bern, 1st edition, pp. 109-119.
• Christie MJ & Vaughan CW (2001) Neurobiology- Cannabinoids act backwards. Nature (London). 410, 527-530.
• Vaughan CW (2001) Cannabis: a pot of cellular actions in the mesolimbic system. Trends in Pharmacological Sciences. 22: 110-111. Also published online as a BioMedNet review (http://reviews.bmn.com).   
  

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