Neuropathic Pain Research
Aim and Concepts
The aim of our research is to investigate the mechanisms underlying chronic neuropathic pain following nervous system injury or autoimmune neuritis, focusing on the involvement of immune cells and their mediators in neuropathic pain.
Nervous system injury such as peripheral nerve injury and spinal cord injury often results in chronic neuropathic pain characterized by spontaneous pain and increases in pain sensitivity. Neuropathic pain is relatively common with an estimated prevalence of 5-7% in the general population and is among the most disabling and expensive burdens in western countries including Australia. During the past two decades, an important focus of pain research has been the study of the mechanisms underlying chronic pain, in particular at the neuronal level. Recently, however, it has become clear that non-neuronal cells including immune and glial cells strongly influence neuronal functions, and thus play a crucial role in neuropathic pain caused by damage to the nervous system.
Fig. 1 – Peripheral nerve injury induces activation of resident immune cells as well as recruitment of inflammatory cells to the nerve. Injury of a peripheral nerve initiates an inflammatory response in which mast cells, neutrophils, macrophages and T cells are recruited and activated, Schwann cell dedifferentiate and all release their mediators such as pro-inflammatory cytokines and contribute to neuropathic pain (Moalem G & Tracey DJ. Brain Res Brain Res Rev 51, 240-264; 2006).
Fig. 2 – Peripheral nerve injury induces glial activation in the dorsal horn of the spinal cord. Injury to a peripheral nerve initiates increased release of neurotransmitters such as glutamate, substance P and ATP from the central terminals of primary afferents. These neurotransmitters can activate both second order neurones and glia, which produce and release inflammatory mediators including pro-inflammatory cytokines (such as TNF and IL-1β), glutamate (Glu), prostaglandins (PGs) and nitric oxide (NO). These agents are then capable of sensitising dorsal horn neurones, thereby contributing to neuropathic pain (Moalem G & Tracey DJ. Brain Res Brain Res Rev 51, 240-264; 2006).
Methods
We use animal models of neuropathic pain and in vitro work to investigate the neuro-immune crosstalk in the injured nervous system.
Experimental techniques include:
- Animal surgery (e.g., peripheral nerve injury, spinal cord injury)
- Animal immunization (e.g., induction of experimental autoimmune neuritis)
- Animal behaviour studies (measuring withdrawal latency to thermal stimuli using a plantar analgesia meter for paw stimulation, and measuring withdrawal threshold to mechanical stimuli using an electronic von Frey anesthesiometer)
- Histological work (fluorescent/confocal microscopy and image analysis)
- Cell culture
- Western blot
- Flow cytometry
- ELISA / Cytokine assays
- Electrophysiology using the technique of in vitro threshold tracking to measure axonal excitability
Current Projects
- Involvement of T cells and their cytokines in neuropathic pain following nerve injury and in experimental autoimmune neuritis
- Immunomodulation of pain behaviours in animal models of chronic pain
- The role of connexin 43 in persistent pain due to peripheral nerve injury
Funding
- Moalem-Taylor G. NHMRC Project Grant ID # 568637; 2009-2011: “The role of proinflammatory interleukin-17 (IL-17) and IL-17 producing T cells in neuropathic pain"
- Moalem-Taylor G. NSW OSMR Career Development Fellowship Research Grant under the NSW Spinal Cord Injury and Related Neurological Conditions Research Grants Program. 2010-2012: “Immunomodulation of neuropathic pain due to peripheral nerve injury or spinal cord injury”
Recent Publications
Moalem G, Xu K & Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience 129: 767-777 (2004).
Moalem G, Grafe P & Tracey DJ. Chemical mediators enhance the excitability of unmyelinated sensory axons in normal and injured peripheral nerve of the rat. Neuroscience 134: 1399-1411 (2005).
Lang PM*, Moalem-Taylor G*, Tracey D, Bostock H & Grafe P. Activity-dependent modulation of axonal excitability in unmyelinated peripheral rat nerve fibers by the 5-HT(3) serotonin receptor. (*Equal contributors) J Neurophysiol 96: 2963-2971 (2006).
Moalem G & Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain. REVIEW. Brain Res Brain Res Rev 51, 240-264 (2006).
Moalem-Taylor G, Allbutt HN, Iordanova MD & Tracey DJ. Pain hypersensitivity in rats with experimental autoimmune neuritis, an animal model of human inflammatory demyelinating neuropathy. Brain Behav Immun 21: 699-710 (2007).
Moalem-Taylor G, Lang PM, Tracey DJ & Grafe P. Post-spike excitability indicates changes in membrane potential of isolated C-fibers. Muscle Nerve 36:172-182 (2007).
Evans S, Moalem-Taylor G & Tracey DJ. Pain and endometriosis. REVIEW. Pain 132 Suppl 1: S22-5 (2007).
Li M, Peake P, Charlesworth J, Tracey DJ & Moalem-Taylor G. Complement activation contributes to leukocyte recruitment and neuropathic pain following peripheral nerve injury in rats. Eur J Neurosci 26: 3486–3500 (2007).
Smith F, Haskelberg H, Tracey DJ & Moalem-Taylor G. Role of histamine H(3) and H(4) receptors in mechanical hyperalgesia following peripheral nerve injury. Neuroimmunomodulation 14: 317-325 (2007) Epub 2008 Apr 10
Austin PJ & Moalem-Taylor G. The neuro-immune balance in neuropathic pain: Involvement of inflammatory immune cells, immune-like glial cells and cytokines. REVIEW. Journal of Neuroimmunology 229:26-50 (2010).
Kim CF & Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. Journal of Pain 12:370-383 (2011).
Hill F, Kim CF, Gorrie CA & Moalem-Taylor G. Interleukin-17 deficiency improves locomotor recovery and tissue sparing after spinal cord contusion injury in mice. Neuroscience Letters 487:363-7 (2011).
Moalem-Taylor G, Li M, Allbutt HN, Wu A & Tracey DJ. A preconditioning nerve lesion inhibits mechanical pain hypersensitivity following subsequent neuropathic injury. Molecular Pain 7(1):1 (2011).
Kim CF & Moalem-Taylor G. Detailed characterization of neuro-immune responses following neuropathic injury in mice. Brain Res. (2011), doi:10.1016/j.brainres.2011.06.022
Austin PJ, Wu A & Moalem-Taylor G. Chronic constriction of the sciatic nerve and pain hypersensitivity testing in rats. Journal of Visualized Experiments (JoVE). In press, accepted April 26, 2011.