Serotonin (5-HT) Modulation of Pain Perception in Humans

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SCIENCE
Serotonin (5-HT) Modulation of Pain Perception in Humans
Key Take-Away: 

Effects of 5-HT on pain perception did not found to be confounded by mood changes.

Pain is an essential learning mechanism which is important for survival and avoiding damage. Pain processing is linked to various regions of brain that integrates information to form a pain matrix. It occurs due to combination of multiple factors such as stimulus intensity, emotional and contextual state and individual past experiences which contributes to the expectation of pain.

ABSTRACT: 
Background: 

Pain is an essential learning mechanism which is important for survival and avoiding damage. Pain processing is linked to various regions of brain that integrates information to form a pain matrix. It occurs due to combination of multiple factors such as stimulus intensity, emotional and contextual state and individual past experiences which contributes to the expectation of pain. There is a high prevalence of chronic pain and limited treatment as compared to acute pain. The preliminary treatment against chronic pain is selective serotonin re uptake inhibitors (SSRIs) that acts by increasing the level of serotonin (5-HT) in the brain. The use of serotonin inhibitors generates mixed results, but their mechanism of action on pain processing is not known. The specific role of 5-HT in the modulation of pain processing is shown by certain animal studies. Descending inhibitory serotonergic spinal-raphe projections arises from raphe magnus of nucleus and an endogenous descending pain-modulating network is formed. The pain-modulating network is capable of mediating both the facilitation and inhibition of nociceptive processing. On the other hand, ascending serotonergic pain pathways projects from midbrain dorsal-raphe nucleus to limbic and adjacent forebrain sites and controls the attentional processing of nociception.

There is a correlation between chronic pain and maladaptive neuroplastic changes leading to pain sensitivity. It was evident from previous studies that 5-HT levels within the brain can cause abnormal neuroplastic changes associated with chronic pain; however, the role of 5-HT as a modulator in pain perception remains uncertain. The analgesic properties of 5-HT-modulating antidepressants are responsible for role of 5-HT in the pathophysiology of several human chronic pain disorders. There is an uncertainty in apparent analgesic effects of 5-HT-modulating drugs as a direct consequence of increased availability of 5-HT or as a secondary effect of mood changes. A technique called an acute TRP depletion (ATD) that employs the global depletion of its precursor tryptophan (TRP), has been used to determine the role of 5-HT in humans. There was an improvement in pain tolerance and mood with supplementation of TRP in healthy individuals, but still there is a debate on the involvement of mood changes induced by the ATD.

Rationale behind the research

  • There exists a debate concerning the role of 5-HTs in pain perception, so this study was conducted to determine the pain perception associated with use of 5-HTs and examining its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers

Objective

To investigate the utility of ATD in determine the role of 5-HT in pain perception with an attempt to dissociate the effects from mood changes

Methods: 

 

Note: This was a double-blind cross over study.

Study outcome measure

  • Assessment of pain threshold and tolerance determined 4 h post-drink via a heat thermode, additional attention, distraction and temperature discrimination paradigms using a laser-induced heat pain stimulus and mood changes prior and throughout each session.

Time points: Baseline, 4 hours and 6 hours

Results: 

 

Study Outcomes

  • There was a difference of 74.61±13.4% observed between the post-drink concentration of TRP  for BAL (94.20±38.9nmol/mL) and for ATD (19.84±4.4nmol/mL) but no effect of order of the condition was observed (i.e. administration of ATD drink on visit 2 or 3) on the change in TRP levels or LNAA:TRP ratio
  • A higher threshold and tolerance temperature was observed in the BAL condition (threshold 44.00±3.06°C, tolerance 48.87±2.00°C) in comparison to the ATD condition (threshold 43.03±2.77°C, tolerance 47.73±1.86°C)
  • There were no interactions observed between condition and task for low- (F=0.571, p=0.463) or high- (F=0.875, p=0.315) laser stimuli. It indicates that condition of the participant does not adjust the effect of task-induced changes on pain rating
  • There were no effects in any of the mood scores observed between condition (BAL vs. ATD)

Figure 1: Blood Plasma TRP Concentration

Figure 2: The effect of condition on thermode threshold and tolerance temperature

Conclusion: 

The results of this study established a connection between the reduction of global 5-HT via ATD and an alteration of pain perception with altered mood state.

A clear role of 5-HT in pain perception was demonatrated by ATD which significantly reduced both threshold and tolerance of the thermode temperature. Also, ATD significantly affects cognitive appraisal of the sensory-discriminatory aspects of pain, but it did not significantly affect distraction-induced analgesia. The study also supports the paradigm that low levels of 5-HT correlate to pain sensitisation. It is helpful in understanding possible mechanisms of chronic pain states and variable effectiveness seen in the use of SSRIs for chronic pain.

Martin et al. 5-HT modulation of pain perception in humans. Psychopharmacology (2017) 234:2929–2939
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