Endogenous Pain Modulation and Pain Pathway

(Below is rough transcription of the above video)

Endogenous pain modulation is a major aspect of how our bodies govern experience of pain. However before we get into this it’s essential to review the very basics of nociception and pain.

When a bodypart is stimulated in a “painful manner” (and THAT’s pretty subjective to begin with), the sensory neurons called nociceptors will fire off signals to the spine and eventually to the brain. The signal is called NOCICEPTION.

When the nociception is acknowledged by our brain as pain, then we will feel pain. If the nociception is ignored or modulated you either won’t feel pain or feel less pain, and THAT’S despite the PRESENCE of upcoming nociception. And the opposite is also true, so if for some reason the brain decides to FEEL pain even WITHOUT nociception, it certainly will be able to and you’ll experience pain.

So already, that’s half of the endogenous pain modulation answered: CNS is an ACTIVE PARTICIPANT in the pain experience. The opposite of active participation is “passive receiver”. We used to think that the role of the brain is simply to receive the pain signal that’s been generated peripherally and that’s about it.


And unfortunately there are a number of incorrect beliefs that have risen from that thought with some significant consequences for both patients and clinicians. Some of these are:



- amount of pain experienced is directly proportional to the amount of injury (more pain means more harm done, which is often not true

- the source of pain always lies peripherally (which entirely ignores the physiology of endogenous pain modulation)

- and the very source of the pain has to be found in order to address the pain (excessively looking for “where it is coming from” and thus becoming fixated onto investigations such as X-ray and MRI)



Beliefs such as these are easy to understand, and even a lot of health professionals still hold them true. And while they won’t matter for simpler injuries, when it comes to complex or chronic pain, such beliefs will NOT help.

So, let’s review HOW the CNS actively participates in the pain experience. It participates through modulation and facilitation. It’s a continuum of the same concept so let’s just call it modulation for now. And we call this endogenous pain modulation.
I can summarise the modulation into four centres:

- Segmental (14,16)
- Lower centres (Brainstem) (6,14)
- Higher centres (Cerebrum) (6,14)
- Hormonal (2, 7)

Segmental is where non-nociceptive afferent stimulation can inhibit ascending nociceptive signals at dorsal horn. What this means is the sensory neurons responsible for something OTHER than pain, like touch or pressure, can intercept pain signals at spine. This is essentially how you feel better when you rub on a sore spot.

Lower centres or brainstem is responsible for sending pain modulatory signals DOWN the spine. One of the mechanisms that have been identified is called Descending Nociceptive Inhibitory Control (DNIC), and this gets triggered when a new nociception is stimulated while you ALREADY have an ongoing nociception.

These mechanisms from the brainstem suppress the incoming nociception by sending pain-modulating neurotransmitters DOWN the spine, therefore dulling the signals coming up to the brain. The activation of this is also very closely related to the next centre of pain modulation, which is…

Higher centres. This is the bit that makes humans apparently smarter. And this is also where expectations, beliefs, attitudes and other affective constructs are created, and influence pain. They influence pain by directly altering the involvement of cortical regions as well as the lower centres or brainstem that I have just mentioned, particularly periaqueductal grey.

This will result in descending modulatory mechanisms down the spine as I have discussed earlier. The Higher centres also has very close links with the behaviour of autonomic nervous system which plays the major role in the next centre of pain modulation, and that is

Hormonal controls. It is no secret that hormones are incredibly influential when it comes to the behaviour of a body, and they can have a major impact on pain modulation or facilitation. Some of the hormones that are often mentioned here are noradrenaline, adrenaline, cortisole, and dopamine. While I would love to say that “increase in this hormone increases modulation and increase in that hormone increases facilitation etc”, it is not that simple, and I certainly lack the expertise to go into finer details.

There is one more factor to mention, and that is neuroimmunological system. This is not so much a modulation centre but worth mentioning due to its emerging relevance. Certain immune cells can release neurotransmitters that can potentially FACILITATE pain to a great extent.

The recent literature points that the infiltration of these immune cells can have a massive impact on pain processing at the CNS (that’s at both the spinal cord and the brain), making the whole thing more sensitive to pain and counter pain modulation efforts of the body.

The main reason behind the importance of understanding these pain modulation centres is their likely RELEVANCE in most chronic or persisting pain conditions, whether that may be fibromyalgia, arthritis, headache and facial pain, persisting back or neck pain or irritable bowel syndrome.

The past and current literature collectively point to the centres that I have discussed, and the success of rehabilitation of pain conditions depend on patients’ understanding of these concepts, and practical application of the knowledge both by the patients and the clinicians.


2. Corrigan FM, Fisher JJ, Nutt DJ. Autonomic dysregulation and the Window of Tolerance model of the effects of complex emotional trauma. J Psychopharmacol. 2011;25(1):17-25.

6. Goffaux P, Redmond WJ, Rainville P, Marchand S. Descending analgesia--when the spine echoes what the brain expects. Pain. 2007;130(1-2):137-43.

7. Janig, W., Levine, J.D. (2013). Autonomic, Endocrine, and Immune Interactions in Acute and Chronic Pain. In S. K. McMahon, M. Koltzenburg, I. Tracey, & D. Turk (Eds), Wall and Melzack's Textbook of Pain (6th ed., pp. 199-206). Philadelphia: Elsevier Saunders.

13. Main CJ, Sullivan MJL, Watson PJ. Models of pain and disability.  Pain Mangement, Practical applications of the biopsychosocial perspective in clinical and occupational settings. 2nd ed. Edinburgh: Churchill Livingstone Elsevier; 2008. p. 3-27.

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And on neuroimmunology:


Grace, P. M., Hutchinson, M. R., Maier, S. F., & Watkins, L. R. (2014). Pathological pain and the neuroimmune interface. Nat Rev Immunol, 14(4), 217-231. doi:10.1038/nri3621Treede, R. D., Rief, W., Barke, A., Aziz, Q., Bennett, M. I., Benoliel, R., . . . Wang, S. J. (2015). A classification of chronic pain for ICD-11. Pain, 156(6), 1003-1007. doi:10.1097/j.pain.0000000000000160