Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes

Abstract

Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.

Pain sensitivity at rest and during muscle contraction in persons with rheumatoid arthritis: a substudy within the Physical Activity in Rheumatoid Arthritis 2010 study

“…Furthermore, patients with FM showed hyperalgesia and no activation of pain-inhibitory mechanisms, segmental or plurisegmental, during static muscle contractions. Rather, an increase in pain sensitivity was seen [ 10 , 13 ]. Patients with shoulder myalgia showed an activation of the pain-inhibitory mechanisms when contracting a non-painful muscle distant to the pain but a lack of activation when contracting the painful muscle [ 13 ].…”

“…Recently, a genetic association study in humans showed that genetically inferred increased opioid signalling in combination with decreased serotonergic signalling produced better EIH in HC as well as in patients with fibromyalgia (FM). The study revealed antagonistic interactions between opioid and serotonergic signalling upon EIH [ 10 ]. On a behaviour level, exercise activates pain-inhibitory mechanisms in healthy persons with subsequent increase of pain thresholds during muscle contraction [ 11 ].…”

“…On a behaviour level, exercise activates pain-inhibitory mechanisms in healthy persons with subsequent increase of pain thresholds during muscle contraction [ 11 ]. Persons with central sensitisation who were diagnosed with, for example, FM or FM with comorbid chronic fatigue syndrome respond differently [ 9 , 10 , 12 – 14 ], owing to a dysfunction of endogenous pain-inhibitory mechanisms during exercise (i.e., dysfunctional EIH). In patients with osteoarthritis (OA) in the hip or knee, we found increased pain sensitivity but normal function of EIH during muscle contractions [ 15 ].…”

The genetics of pain: a bio-psycho-SOCial approach for understanding pain

“…SLC6A4 encodes the membrane protein responsible for transporting serotonin from synaptic spaces to pre-synaptic neurons. It has been studied for its role in depression-susceptibility in people experiencing emotional trauma [5]. The protein encoded by the FKBP5 gene is a member of the immunophilin protein family.…”

“…This family of proteins is heavily involved in regulating the immune system, as well as playing a role in basic cellular processes such as protein folding and trafficking [6]. The OPRM1 gene makes a protein known as the mu (µ) opioid receptor, which is important for regulating reward, pain, and addictive behaviours in our bodys opioid system [5].…”