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Written by

Dr Luis Villanueva

Dr Luis Villanueva, is director of research at INSERM UMR 894, Center of Psychiatry and Neuroscience, Paris, France​.

What's new in pain research?

Published 15 July 2017

Dr Luis Villanueva describes how animal models and clinical findings have shown that pain perceptions are under strong influences of brain modulation mechanisms

Key points

  • The features of acute or chronic pain experience result from close interactions between bottom-up and top-down brain modulation mechanisms.
  • These interactions elicit dynamic functional states in the brain at the origin of long-term modifications of the excitability of the pain matrix.
  • Such complex regulations may produce a high variability of pain perceptions under similar clinical situations and influence the outcome of therapeutic strategies.

Diffuse noxious inhibitory control (DNIC) mechanisms and conditioned pain modulation (CPM): translational tools for detecting putative pain biomarkers

Animal studies of DNIC have shown that any kinds of acute painful stimuli activate descending inhibitory controls originating in the brainstem, acting on spinal neurons conveying noxious messages to the brain.1 DNIC mechanisms mediate the ‘pain inhibits pain’ phenomenon observed in healthy humans. 

The CPM term describes functional explorations of the inhibition of pain by a distant painful stimulus in patients, showing that DNIC mechanisms differ in health and disease. The effects of CPM on temporally and spatially summated pain diminish in patients with varied pain syndromes, including fibromyalgia, migraine, tension headache and irritable bowel syndrome.2 A reduced inhibitory efficiency also occurs in osteoarthritis patients with pain, and improvement of the CPM efficiency occurs in parallel to pain relief after surgery.3 In addition, significant reductions of CPM are revealed to be predictive of chronic postoperative pain.4 

A loss of DNIC strength is also present in painful diabetic neuropathy patients, where CPM predicts the efficacy of duloxetine, a serotonin-norepinephrine reuptake inhibitor. Patients with less efficient CPM experienced highly efficacious pain reduction, while those with efficient CPM did not benefit from the treatment.5 

Recent studies in neuropathic rodents shed light on the implication of monoaminergic mechanisms in the reduction of DNIC. A variety of electrophysiological and pharmacological experiments showed that a loss of DNIC elicited from the neuropathic limb can be restored following local (spinal), but not systemic delivery of SSRIs (citalopram or fluoxetine). In addition, augmentation of spinal serotonin concentrations, which restore DNIC, is mediated through 5-HT7 receptors and is dependent on an underlying tonic inhibitory tone via alpha-2 adrenoceptor signalling systems.6,7

Conclusions

Taken together, animal and human studies support the concept that central networks that process pain do not merely consist of a single bottom-up process whereby a painful focus amplifies the inputs to the next higher level. Indeed, several brain regions mediate subtle forms of plasticity by continuously adjusting neural maps downstream and consequently altering all the modulatory mechanisms at the origin of pain experiences.8 

Disturbances in normal pain processing (the ‘alarm system’) within these networks by comorbidity mechanisms could lead to maladaptive changes, impairing sensory, affective and cognitive processes with consequent modifications in varied aspects of pain perception and reactions.8,9 A better understanding of ‘bottom-up’ and ‘top-down’ interactions should contribute to successful developments of therapeutic strategies aimed at improving life quality of patients suffering from impaired brain modulation leading to chronic pain. 


  • Dr Luis Villanueva, is director of research at INSERM UMR 894, Center of Psychiatry and Neuroscience, Paris, France.

References

  1. Bourgeais L, Arreto C, et al. Pain 2014 Refresher Courses, IASP Press, 2014; 419-30.
  2. Yarnitsky D Current Opinion in Anaesthesiology 2010;23(5):611-615.
  3. Kosek E, Ordeberg G. Pain 2000;88(1):69-78.
  4. Yarnitsky D, Crispel Y, et al. Pain 2008;138(1):22–28.
  5. Yarnisty D, Granot M, et al. Pain 2012;153(6):1193-1198.
  6. Bannister K, Patel R, et al. Pain 2015; 156(9):1803-1811.
  7. Bannister K, Lockwood S, et al. European Journal of Pain 2017;21(4):750-760.
  8. Baliki M, Apkarian AV. Neuron 2015 87(3):474-491.
  9. Attal N, Masselin-Dubois A, et al. Brain 2014 137(Pt 3): 904-917.

Date of preparation: July 2017; MINT/PAEU-17031