Excitation & Inhibition - A Critical Balance

8th Annual Lindahl Lecture: 

Excitation & Inhibition - A Critical Balance

Target Audience

This activity is designed for clinicians and researchers utilizing or developing therapies with application to the nervous system. 

This activity may benefit anyone with a lack of understanding of the role that excitation and inhibition play within the nervous system; how improper or maladaptive 'tuning' or 'balance' of these impulses contributes to disease formation or treatment.

Learning Objectives

The inhibitory systems within the CNS can be activated by brain stimulation, intracerebral microinjection of morphine, and peripheral nerve stimulation. 

Of Specific Relevance to the Study and Treatment of Pain

Excitation and inhibition are central to the development and treatment of pain. Pain information in the CNS is controlled by ascending and descending inhibitory systems and studies have shown that patients with painful neuropathy have an excitatory/inhibitory neurotransmitter imbalance in the brain. Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury.

Understanding pain mechanisms is key to the development of novel analgesics and to better use of existing agents.  Spinal inhibition may be impaired under conditions of neuropathy and inflammation, and the available evidence suggests that disinhibition in the spinal dorsal horn may lead to characteristic symptoms of neuropathic pain such as hyperalgesia, dynamic mechanical allodynia, and spontaneous paroxysmal pain. Centrally acting analgesic drugs activate these inhibitory control systems.

The concepts explored in detail here are supported and be expanded upon in other activities by Drs. Fillingim, Cheng and Guan.

Desirable Physician Attributes

• Medical Knowledge [ACGME/ABMS] (about established and evolving biomedical, clinical, and cognate (e.g. epidemiological and social-behavioral) sciences and the application of this knowledge to patient care)
  
• Employ Evidenced-based Practice [IOM]   Integrate best research with clinical expertise and patient values for optimum care, and participate in learning and research activities to the extent feasible
• Utilize Informatics [IOM] Communicate, manage, knowledge, mitigate error, and support decision making using information technology

Pain management domains and core competencies

• 1. Multidimensional nature of pain: What is pain?
  • 1.1: Explain the complex, multidimensional, and individual-specific nature of pain
  • 1.2: Present theories and science for understanding pain
  • 1.3: Define terminology for describing pain and associated conditions

• 3. Management of pain: How is pain relieved?
  • 3.5:  Monitor effects of pain management approaches to adjust the plan of care as needed
  • 3.7: Develop a treatment plan that takes into account the differences between acute pain, acute-on-chronic pain, chronic/persistent pain, and pain at the end of life

Accreditation & Designation

Release date: This activity was released 8/15/2020.

Termination date: The content of this activity remains eligible for CME Credit until 8/14/2023, unless reviewed or amended prior to this date.

Neurovations Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Neurovations Education designates this other activity (blended learning) for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure of Financial Relationships

Neither the speaker, peer reviewers nor any other person with control of, or responsibility for, the development, management, presentation or evaluation of the CME activity has, or has had within the past 12 months, any relevant financial relationships to disclose. This includes any relationships of an involved person's spouse/partner.

Additional Reading

• Rosenberg, R. N., & Pascual, J. M. (Eds.). (2020). Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1. Academic press.
• Pelletier, R., Higgins, J., & Bourbonnais, D. (2015). Is neuroplasticity in the central nervous system the missing link to our understanding of chronic musculoskeletal disorders?. BMC Musculoskeletal Disorders, 16(1), 25.
• Petrou, M., Pop-Busui, R., Foerster, B. R., Edden, R. A., Callaghan, B. C., Harte, S. E., ... & Feldman, E. L. (2012). Altered excitation-inhibition balance in the brain of patients with diabetic neuropathy. Academic Radiology, 19(5), 607-612.
• Abbott, L. F., & Nelson, S. B. (2000). Synaptic plasticity: taming the beast. Nature Neuroscience, 3(11), 1178-1183.
• Vogels, T. P., Rajan, K., & Abbott, L. F. (2005). Neural network dynamics. Annu. Rev. Neurosci., 28, 357-376.
• Goffer, Y., Xu, D., Eberle, S. E., D'amour, J., Lee, M., Tukey, D., ... & Wang, J. (2013). Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state. Journal of Neuroscience, 33(48), 19034-19044.
• Song, S., & Abbott, L. F. (2001). Cortical development and remapping through spike timing-dependent plasticity. Neuron, 32(2), 339-350.
• Song, S., Miller, K. D., & Abbott, L. F. (2000). Competitive Hebbian learning through spike-timing-dependent synaptic plasticity. Nature Neuroscience, 3(9), 919-926.
• Latremoliere, A., & Woolf, C. J. (2009). Central sensitization: a generator of pain hypersensitivity by central neural plasticity. The Journal of Pain, 10(9), 895-926.
• Mainen, Z. F., & Abbott, L. F. (1999). Functional plasticity at dendritic synapses. In Dendrites (pp. 310-338). Oxford University Press, Oxford.
• Sussillo, D., & Abbott, L. F. (2009). Generating coherent patterns of activity from chaotic neural networks. Neuron, 63(4), 544-557.
• Gold, M. S., & Gebhart, G. F. (2010). Nociceptor sensitization in pain pathogenesis. Nature Medicine, 16(11), 1248-1257.
• Potter, L. E., Paylor, J. W., Suh, J. S., Tenorio, G., Caliaperumal, J., Colbourne, F., ... & Kerr, B. J. (2016). Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis. Journal of Neuroinflammation, 13(1), 142.
• Staud, R. (2013). The important role of CNS facilitation and inhibition for chronic pain. International journal of Clinical Rheumatology, 8(6), 639.
• Sandkühler, J. (2009). The role of inhibition in the generation and amplification of pain. In Current Topics in Pain: 12th World Congress on Pain (pp. 53-71).
• Burke, N. N., Finn, D. P., McGuire, B. E., & Roche, M. (2017). Psychological stress in early life as a predisposing factor for the development of chronic pain: clinical and preclinical evidence and neurobiological mechanisms. Journal of neuroscience research, 95(6), 1257-1270.