Receptors and proteins involved in gender pain
Recettori e proteine coinvolti nel dolore di genere
Pathos 2018; 25; 2. Online 2018, June 26
Francesco Amato,1 Erminia Gilda Morrone 2
1 Direttore UOC Terapia del Dolore e CP Azienda Ospedaliera Cosenza, Italy
2 Biologa, Associazione Centro Studi Terapia del Dolore, Cosenza, Italy
Riassunto Nel corso dei secoli è stato generalmente accettato che le donne costituiscano il genere più sensibile. Recenti studi hanno mostrato ulteriori conferme; le donne, infatti, presentano dei recettori sulle fibre nervose che, legandosi agli estrogeni, le rendono più sensibili degli uomini. La gravidanza, con l'aumento del progesterone, può alleviare il dolore come mostra il testo.
Summary Over the centuries it has generally been accepted that women are the most sensitive gender. Recent studies have shown further confirmations; in fact, women have receptors on nerve fibers that, by binding to estrogens, cause them to feel pain more intensely than men. Pregnancy, with the increase of progesterone, can relieve pain as the text shows.
Parole chiave estradiolo, testosterone, gravidanza, TRPV1, dolore
Key words estradiol, testosterone, pregnancy, TRPV1, pain
Gender medicine represents a new medical approach to treat people.
The target of gender medicine is to understand the mechanisms by which gender-related differences act on the state of health and on the onset and course of many diseases as well as on the results achieved. Women show a greater sensitivity to pain: they suffer more often and pain lasts longer and is reported as more intense. This most likely correlates to physiological differences (genetic and hormonal) and psycho-social factors. This greater sensitivity most likely correlates to physiological differences (genetic and hormonal) and to psycho-social factors.
According to a survey carried out on more than 85 thousand adults in 17 countries all over the world, chronic pain affects 45% of women, compared to 31.4% of men, and chronic pain is associated with depression in 8% of cases.1-3 The greater susceptibility to pain manifests itself on both levels, sensitive and emotional.
Anatomical, hormonal and physiological differences are at the basis of a greater possibility of developing pathologies that cause pain and a lower threshold of pain perception than men.
It is also necessary to consider the emotional dimension. A woman has a much intimate relationship with pain, since she is often involved in the suffering of others, thus becoming particularly empathetic and sensitive to the phenomenon.
Many studies conducted in the last decades, which examined the pathogenesis of neuropathic pain and its prevention and treatment strategies, confirmed that pain threshold is specific in relation to gender. Estrogen receptors are distributed in many pain-related regions in central and peripheral nervous systems, and estrogens can influence pain generation and transmission to many levels.4,5
Recently, a link between the estrogens and the N-methyl-D-aspartic acid receptor 1 receptor (NMDAR1 a receptor subtype) has been observed. Glutamate is linked to an excitatory neurotransmitter involved in the generation, transmission and maintenance of various types of pain.6-11
In particular, NMDAR1 plays a primary role in transmission and regulation of information regarding neuropathic pain.12-14 It appears that NMDA receptor NMDAR1 subunits occupy a key position in the development of neuropathic pain15,16 and that the administration of the specific antagonist NMDAR1 AP-5 could reduce the upregulation of estrogen-induced NMDAR1 expression to significantly improve the pain threshold in the guinea pigs.
In conclusion, during chronic neuropathic pain, estrogen can increase the body's sensitivity to mechanical and thermal stimulation by increasing the expression of NMDAR1.17
Payrits et al18 also highlighted how gender differences also affect chronic pain and gonadal estradiol (E2) alters the sensation of pain. The vanilloid receptor 1 (TRPV1) plays, in fact, a critical role in triggering pain.
In particular, it was observed that E2 enhances the mechanical hyperalgesia induced by activation of the TRPV1 receptor in ovariectomized guinea pigs.18
A long pretreatment (14 hours) with E2, in fact, induces a significant increase in the messenger RNA expression of the TRPV1 receptor and abolishes the desensitization of capsaicin-induced TRPV1 receptor in primary sensory neurons.
The aforementioned study also provides both in vivo and in vitro tests of the upregulation of the E2-induced TRPV1 receptor and mediated by TrkAR via genomic and non-genomic mechanisms (induced by E2).
Instead, when there is an increase of progesterone (for example during pregnancy) it seems to determine the TRPV1 receptors down-regulation at the plasma membrane of sensory neurons. Renterià et al18 have examined how progesterone, interacting with a Chaperone Sigma 1 Receptors (sig-1R) (molecular Chaperone is a protein that guides the correct three-dimensional folding of some proteins in this case of TRPV1), seems to be down-regulated the expression of TRPV1 at the plasma membrane of the sensory neuron, decreasing the perception of pain in physiological conditions such as pregnancy.19
In the final analysis, Bai et al20 report how testosterone plays a key role in inhibiting TRPV1 expression in the sensory ganglia (in a model of inflammatory chronic pain induced in rats).
Therefore, many experimental tests indicate gender differences for neuropathic and/ or chronic pain, both in humans and in animals. Future clinical trials will attempt to identify functional genetic variants within the loci and associated molecular mechanisms; this will result in a better understanding of individual responses to therapy and in a new development of pharmacotherapy and devices. Understanding the conformational changes that occur in these proteins when a ligand binds and activates the receptor or genetic variations related to the aforementioned receptor protein, as well as genomic profiling linked to sex, should facilitate the development of potential drugs with fewer side effects and pharmacological properties more favorable. We will witness a real paradigm shift, to make a contribution to gender medicine and to the development of personalized healthcare, tailored to women and men.
Conflict of interest
The authors certify the study was conducted without conflicts of interest.
26th June 2018
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