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Gender and genetic variations as background of placebo analgesia

The placebo analgesia has been one of the most extensively studied placebo effects since the 19th century. One of the major placebo analgesia effect noted was in World War II when saline infusion given to soldiers induced the same pain-relief effect as morphine. This fact has initiated further research. Intriguing question is why placebo induces positive response among some people, while for the others it doesn’t stimulate any changes or even stimulate negative response - nocebo. Even more fascinating is the fact that gender differences affect the pain response. In the last few decades, scientists have conducted brain imaging and genetic studies to uncover the cause of sex-related differences in placebo analgesia. They found that genes and hormones, as well as psychological factors influence pain response. Recent studies have shown that placebo interventions effectively reduce pain, both in healthy women and men, but with various mechanisms of responses to pain. Many research revealed remarkably sexually dimorphism regarding hormonal, neurotransmitter and other receptor’s response. The pain is modulated by µ- and ĸ-opioid, monoamine, GABA and D3/D5 receptors. It was shown that men had higher activation of µ-opioid receptors than women in the thalamus, amygdala and ventral basal ganglia, while women had lower activity in the nucleus accumbens. This is one of the possible reasons why placebo analgesia in men is more noticable. The other reason is indeed difference in sex hormones, with many research providing evidence that estrogens and progesterone seem to be crucial in determining the efficacy of women endogenous inhibitory controls. Also, women’s testosterone levels are positively correlated with the activation of structures implicated in descending inhibitory pathways, such as the rostral ventromedial medulla. Studies about visceral placebo analgesia in IBS patients, in comparison with healthy controls, revealed higher activation in pain-matrix, which includes cingulate cortex, insula, somatosensory cortex and prefrontal cortex. It was also shown that woman and man had comparable results in placebo analgesia in visceral pain, but women have weaker response in descending pain inhibitory mechanism, which involves the insula and dorsolateral prefrontal cortex. In addition to that, genetic polymorphism screening is getting notable lately, with evidence that genetic variations in genes such as COMT, MAO-A, BDNF and OPRM1 might influence placebo response. To conclude, although numerous placebo analgesia studies revealed important evidence about neurobiology of placebo effect, the need for further studies still remains. With precise knowledge of all the mechanisms involved in placebo effect, we might discern placebo responders from non-responders, personalize treatments and more efficiently distinguish drug effects from placebo effects .

placebo, placebo analgesia, sex hormones, visceral pain

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