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Nails in the coffin



This year’s theme focuses on increasing the awareness of clinicians, scientists, and the public of our growing pain knowledge and how it can benefit those living with pain.

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BIM invited me to add my “two pennyworth” (two cents worth for the rest of you!) following Lorimer’s series of excellent blogs. Despite his protestation there is no going back……., the end of neurocentricity is nigh!

No one interested in the subjects that Lorimer focused on in his blogs, learning, memory and neuroplasticity (the clue is in the name) would seriously suggest that the nervous system’s role is not essential but, and it is a big BUT, that due to our need to compartmentalise thinking and establish isolated fields of study (particularly in medicine to allow for specialisms) we have overlooked the critical synergy between the immune and nervous systems and more importantly that the nervous system and immune system are one and the same.

Lorimer’s blogs focused primarily on the role of cytokines, small soluble proteins that act as communication molecules between cells, tissues and organs.  Our knowledge of their actions expands daily; the narrow view that they were confined to roles in innate and specific immune responses is now seriously out of date.  It is well known that many cell types synthesise and release cytokines most notably T cells and macrophages, less well known is that both peripheral and central nervous system neurons are able to produce cytokines and release them in a controlled fashion. These processes usually manifest themselves as part of a repertoire of plastic adaption to a change in homeostasis i.e. a response to a change in cellular demand. My own doctoral studies assessed the potential for neuronal injury to produce a specific chemokine (a chemokine is a special type of cytokine that is known to attract specific immune cell types i.e. chemoattractant cytokine) CCL2 which we Thacker et al (1) and others (see 2-5 for excellent reviews) demonstrated is involved in the production of responses which are thought to be associated with neuropathic pain. What is apparent from this and other work is that whilst cytokines are produced by immune cells under basal (normal) conditions they are not normally synthesised at bioactive levels in healthy neurons other than during specific periods of neural development. Following damage to neurons (particularly nociceptors) the genetic apparatus of the neuron is activated and the neuron changes its phenotype (the set of characteristics it normally displays) from synthesizing only molecules to do with “nervy” stuff to synthesising molecules which are involved in “immuny” stuff! (see 6). The neurons have become immune cells or more accurately they always were i.e. they had the capability to be function in both a “nervy” and “immuny” state. Not only that but they begin to use these de novo (newly expressed) cytokines as neurotransmitters as well as to directly activate immune cells in the immediate vicinity (see 1, 3-5).

The majority of work reviewed by Lorimer assumes that the observed alterations in cytokine levels arise as a result of local up or down regulation of specific cytokines by non-neuronal cells such as glia and astrocytes, whilst these cells have been repeatedly shown to be a source of cytokines, the role and importance of neuronal derived cytokines remains to be assessed in the mechanisms of learning and memory. Whilst our understanding of this process is slightly more advanced in the dorsal horn of rodents following neuronal damage (associated with responses including pain) we know little about neuronally derived cytokines within the brain and importantly anywhere in the nervous systems of humans!

Increasing our knowledge of these processes would have several conceivable benefits, most notably stopping the current trend for therapies that indiscriminately target specific cytokines regardless of their source and which show a lack of understanding of the pleiotropic (has numerous roles) behaviours of cytokines; and lead to the development and implementation of endogenous strategies which directly target these mechanisms which could include boosting or inhibiting neuronal derived cytokines. Alterations in cytokines levels within the nervous system are also associated with several neurodegenerative diseases including Alzheimer’s and Parkinson’s; neuropathologies such as MS; mental illnesses i.e. depression and schizophrenia; neurobehavioural discorders including OCD and AHAD; therefore any benefits derived from increasing our knowledge and changing perspectives offer the potential for solutions that cross disciplines and just might put the final nail in the coffin of neurocentricity.

(………  Maybe this way of thinking also hails the death of immunocentricity!)

About Mick

Dr Mick Thacker is widely regarded as the words nicest clever person.  He started his PhD under the veritable godfather of pain science Professor Patrick Wall and has continued to forge a path towards a better understanding of the role of the immune system in chronic and neuropathic pain.  He currently runs the Kings College London masters of pain science programme. He knows more about dragon flies than most people in the world and he knows more about the immune system than he does about dragon flies.


[1] Thacker, M., Clark, A., Bishop, T., Grist, J., Yip, P., Moon, L., Thompson, S., Marchand, F., & McMahon, S. (2009). CCL2 is a key mediator of microglia activation in neuropathic pain states European Journal of Pain, 13 (3), 263-272 DOI: 10.1016/j.ejpain.2008.04.017

[2] Thacker, M., Clark, A., Marchand, F., & McMahon, S. (2007). Pathophysiology of Peripheral Neuropathic Pain: Immune Cells and Molecules Anesthesia & Analgesia, 105 (3), 838-847 DOI: 10.1213/01.ane.0000275190.42912.37

[3] McMahon, S., & Malcangio, M. (2009). Current Challenges in Glia-Pain Biology Neuron, 64 (1), 46-54 DOI: 10.1016/j.neuron.2009.09.033

[4] Abbadie, C., Bhangoo, S., De Koninck, Y., Malcangio, M., Melik-Parsadaniantz, S., & White, F. (2009). Chemokines and pain mechanisms Brain Research Reviews, 60 (1), 125-134 DOI: 10.1016/j.brainresrev.2008.12.002

5) Schafers M., Sommer C., Sorkin L. (2007) Proinflammatory cytokines and neuropathic pain: Retrograde signaling in dorsal root ganglion changes after peripheral nerve injury. In (DeLeo J.A.,Sorkin L.S., Watkins L.R., Eds.) Immune and glial regulation of pain. IASP Press.

[6] Costigan M, Befort K, Karchewski L, Griffin RS, D’Urso D, Allchorne A, Sitarski J, Mannion JW, Pratt RE, & Woolf CJ (2002). Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC neuroscience, 3 PMID: 12401135

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