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Chronic Pain: Lost Inhibition?



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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While working with chronic neuropathic pain sufferers over the last few years, quite often I was asked if there is a “pain center” within our body, particularly in the brain, where pain is generated. One of my chronic pain patients actually quipped: “If you tell me where the pain hub is I will go to a surgeon and let them cut it out”. Unfortunately, there is no simple answer as multiple factors play a role in the development and maintenance of chronic pain. However, there is interesting work published which suggests that neuropathic pain may be maintained by a discrete central generator, possibly within the thalamus.

Indeed, over 30 years ago, it was suggested by Melzack and Loeser (1978) following observations in subjects with chronic neuropathic pain following spinal cord injury (SCI) that: “once abnormal central pattern generating processes are underway, peripheral contributions may assume less importance.” They proposed that chronic pain results from neural processes within the brain itself and suggest that only by targeting the activity of this central pattern generator will we be able to effectively tackle the problem of chronic pain.

Consistent with these early observations, we have shown that neuropathic pain following SCI is associated with significant plastic changes in the anatomy of a number of brain regions including the area of the thalamus (Gustin et al, 2010). In addition, we have demonstrated that painful trigeminal neuropathic pain is associated with anatomical and chemical changes within a specific part of the thalamus called the ventroposterior (VP) thalamus (Gustin et al. 2011).

The VP thalamus is the crucial brain processing centre that distributes nociceptive (painful) information to the cerebral cortex where pain perception is thought to occur. We can simply label it the “gateway to the cortex”. In addition to its role in acute pain, there are a number of lines of evidence to indicate that the VP thalamus is involved in the generation and maintenance of chronic neuropathic pain:

  • First, small localized stroke lesions within the VP thalamus may result in a form of chronic pain called central pain (Kim et al. 2007).
  • Second, electrophysiological (Lenz et al. 1989) and biochemical (Pattany et al. 2002) studies have demonstrated thalamic changes in neuropathic pain following cerebral infarct and spinal cord injury.
  • Third, voxel-based morphometry studies show gray matter volume and density decreases in the thalamus in patients with chronic back pain, phantom pain, migraine, tension-type headache, and fibromyalgia (Costigan et al. 2009; May 2008)

In accordance with this line of evidence we wanted to look closer at the thalamus. So, our first question was how we can explore changes in thalamic function in humans with chronic pain? Fortunately, recent developments in magnetic resonance imaging (MRI) techniques allow for the investigation of brain anatomy, function and biochemistry in humans with chronic pain. Consequently, we wanted to use the following techniques in our study:

  • Changes in thalamic anatomy can be determined using the technique of voxel based morphometry, which can be used to assess changes in gray matter volume.
  • Changes in thalamic activity can be determined using the techniques of quantitative arterial spin labelling and resting state functional MRI. These functional MRI techniques can be used to provide absolute levels of regional blood flow and to evaluate regional brain interactions.
  • Finally, thalamic anatomy and activity can be assessed using magnetic resonance spectroscopy (MRS). MRS can be used to explore changes in regional chemicals associated with neural viability. In particular, we were interested in the chief inhibitory neurotransmitter in the central nervous system, gamma amino butyric acid (GABA).

Thus, in our recent study (Henderson et al. 2013), we used all the above described brain imaging techniques to explore brain changes, particularly in the thalamus, in subjects with painful trigeminal neuropathic pain (PTN). Our results revealed that individuals with ongoing neuropathic pain displayed significant VP thalamus volume loss (voxel-based morphometry) which was associated with decreased thalamic reticular nucleus (TRN) activity (quantitative arterial spin labeling). Furthermore, thalamic inhibitory neurotransmitter content (GABA) was significantly reduced (MRS spectroscopy), which was significantly correlated to the degree of functional connectivity between the VP thalamus and various cortical regions (resting state functional MRI).

Taken together, our results showed that a loss of VP thalamus neurons, that send information to the cortex, result in a decreased excitatory input to the TRN. As a consequence of this decreased TRN activity, the content of inhibitory neurotransmitter content (i.e. GABA) within the thalamus is reduced. This reduction in TRN inhibitory output may result in disturbances to central processing which may result in the constant experience of pain.

Having just described the outcome of our recent study in a very scientific language, for all the non-scientists among us, we offer a more simplified explanation. Our study showed that inhibitory brain cells (which normally block out pain) within the thalamus may have reduced functioning in individuals with ongoing pain. As a result there is a reduction of blood flow in the thalamus and the amount of the chief inhibitory messenger of neurologic information from one cell to another, i.e. GABA, is decreased. This loss of inhibition may mean that the brain itself is altered which results in brain activity changes that are then perceived as pain.

About Sylvia Gustin

Having completed a PhD in Psychology at the Institute of Medical Psychology & Behavioural Neurobiology, University of Tuebingen, Germany, Sylvia is currently working in Sydney at the Department of Anatomy & Histology, University of Sydney. Sylvia is an eager researcher, aiming to enrich our understanding of the development and maintenance of chronic pain and to develop therapy strategies for the many sufferers of chronic pain conditions.


Melzack R, & Loeser JD (1978). Phantom body pain in paraplegics: evidence for a central “pattern generating mechanism” for pain. Pain, 4 (3), 195-210 PMID: 273200

Gustin SM, Wrigley PJ, Siddall PJ, & Henderson LA (2010). Brain anatomy changes associated with persistent neuropathic pain following spinal cord injury. Cerebral cortex, 20 (6), 1409-19 PMID: 19815621

Gustin SM, Peck CC, Wilcox SL, Nash PG, Murray GM, & Henderson LA (2011). Different pain, different brain: thalamic anatomy in neuropathic and non-neuropathic chronic pain syndromes. J Neurosci, 31 (16), 5956-64 PMID: 21508220

Kim JH, Greenspan JD, Coghill RC, Ohara S, & Lenz FA (2007). Lesions limited to the human thalamic principal somatosensory nucleus (ventral caudal) are associated with loss of cold sensations and central pain. J Neurosci, 27 (18), 4995-5004 PMID: 17475808

Lenz FA, Kwan HC, Dostrovsky JO, & Tasker RR (1989). Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain research, 496 (1-2), 357-60 PMID: 2804648

Pattany PM, Yezierski RP, Widerström-Noga EG, Bowen BC, Martinez-Arizala A, Garcia BR, & Quencer RM (2002). Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. AJNR, 23 (6), 901-5 PMID: 12063213

Costigan M, Scholz J, & Woolf CJ (2009). Neuropathic pain: a maladaptive response of the nervous system to damage. Annual review of neuroscience, 32, 1-32 PMID: 19400724

May A (2008). Chronic pain may change the structure of the brain. Pain, 137 (1), 7-15 PMID: 18410991

Henderson, L.A., Peck, C.C., Petersen, E.T., Rae, C., Youssef, A., Reeves, J., Wilcox S.L., Akhter, R., Murray, G.M. and Gustin, S.M. Chronic pain – lost inhibition? J Neurosci 2013: 33(17):7574-82.

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