Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis.

PURPOSE: Several observational studies suggest that estrogens could bias pain perception. To evaluate the influence of estrogenic impregnation on pain expression, a prospective, randomized, controlled, blinded study was conducted in a Sprague-Dawley rat model of surgically induced osteoarthritis (OA). METHODS: Female rats were ovariectomized and pre-emptive 17ß-estradiol (0.025 mg, 90-day release time) or placebo pellets were installed subcutaneously during the OVX procedures. Thirty-five days after, OA was surgically induced on both 17ß-estradiol (OA-E) and placebo (OA-P) groups. Mechanical hypersensitivity was assessed by static weight-bearing (SWB) and paw withdrawal threshold (PWT) tests. Mass spectrometry coupled with high-performance liquid chromatography (HPLC-MS) was performed to quantify the spinal pronociceptive neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), somatostatin (SST), and dynorphin-A (Dyn-A). RESULTS: Compared to control, ovariectomized rats presented higher SP (P = 0.009) and CGRP (P = 0.017) concentrations. OA induction increased the spinal level of SP (+ 33%, P < 0.020) and decreased the release of BK (- 20%, (P < 0.037)). The OA-E rats at functional assessment put more % body weight on the affected hind limb than OA-P rats at D7 (P = 0.027) and D56 (P = 0.033), and showed higher PWT at D56 (P = 0.009), suggesting an analgesic and anti-allodynic effect of 17ß-estradiol. Interestingly, the 17ß-estradiol treatment counteracted the increase of spinal concentration of Dyn-A (P < 0.016) and CGRP (P < 0.018). CONCLUSION: These results clearly indicate that 17ß-estradiol interfers with the development of central sensitization and confirm that gender dimorphism should be considered when looking at pain evaluation.

Insights into the mechanisms and the emergence of sex-differences in pain.

Recent studies describe sex and gender as critical factors conditioning the experience of pain and the strategies to respond to it. It is now clear that men and women have different physiological and behavioral responses to pain. Some pathological pain states are also highly sex-specific. This clinical observation has been often verified with animal studies which helped to decipher the mechanisms underlying the observed female hyper-reactivity and hyper-sensitivity to pain states. The role of gonadal hormones in the modulation of pain responses has been a straightforward hypothesis but, if pertinent in many cases, cannot fully account for this complex sensation, which includes an important cognitive component. Clinical and fundamental data are reviewed here with a special emphasis on possible developmental processes giving rise to sex-differences in pain processing.

Triggering Descending Pain Inhibition by Observing Ourselves or a Loved-One in Pain.

OBJECTIVES: Recent studies demonstrate that empathy-evoked brain responses include the activation of brainstem structures responsible for triggering descending pain inhibition. Unfortunately, direct evidence linking empathy for pain and descending inhibitory controls (conditioned pain modulation) is lacking. This study, therefore, aimed to determine if the observation of ourselves or a loved-one in pain could activate descending pain inhibition without exposure to a noxious stimulation; which is otherwise required. METHODS: Descending pain inhibition was triggered by immersing the right arm of participants (15 heterosexual couples; mean age±SE: 28.89±2.14) in a bath of cold water. The effects of empathy on descending pain inhibition were observed by immersing the right arm of participants in a bath of lukewarm water while having them watch a video of either themselves or their spouse during a previous nociceptive immersion. Immersion of the arm in a bath of lukewarm water without empathic (video) observation was also included as a control condition. RESULTS: A strong inhibitory response activated by the mere observation of the video of themselves or their spouse in pain without a nociceptive conditioning stimulus. Associative statistics also showed that strong pain catastrophizing responses while watching the video resulted in stronger pain inhibition. Moreover, high levels of empathy were associated with stronger pain inhibition, but only for women. DISCUSSION: This study showed that observing someone in pain triggers descending pain inhibition. Results also demonstrate how empathy and gender are affecting pain modulation mechanisms.

Multicomponent interdisciplinary group intervention for self-management of fibromyalgia: a mixed-methods randomized controlled trial.

BACKGROUND: This study evaluated the efficacy of the PASSAGE Program, a structured multicomponent interdisciplinary group intervention for the self-management of FMS. METHODS: A mixed-methods randomized controlled trial (intervention (INT) vs. waitlist (WL)) was conducted with patients suffering from FMS. Data were collected at baseline (T0), at the end of the intervention (T1), and 3 months later (T2). The primary outcome was change in pain intensity (0-10). Secondary outcomes were fibromyalgia severity, pain interference, sleep quality, pain coping strategies, depression, health-related quality of life, patient global impression of change (PGIC), and perceived pain relief. Qualitative group interviews with a subset of patients were also conducted. Complete data from T0 to T2 were available for 43 patients. RESULTS: The intervention had a statistically significant impact on the three PGIC measures. At the end of the PASSAGE Program, the percentages of patients who perceived overall improvement in their pain levels, functioning and quality of life were significantly higher in the INT Group (73%, 55%, 77% respectively) than in the WL Group (8%, 12%, 20%). The same differences were observed 3 months post-intervention (Intervention group: 62%, 43%, 38% vs Waitlist Group: 13%, 13%, 9%). The proportion of patients who reported ≥ 50% pain relief was also significantly higher in the INT Group at the end of the intervention (36% vs 12%) and 3 months post-intervention (33% vs 4%). Results of the qualitative analysis were in line with the quantitative findings regarding the efficacy of the intervention. The improvement, however, was not reflected in the primary outcome and other secondary outcome measures. CONCLUSION: The PASSAGE Program was effective in helping FMS patients gain a sense of control over their symptoms. We suggest including PGIC in future clinical trials on FMS as they appear to capture important aspects of the patients' experience. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register ISRCTN14526380.

Altered autonomic nervous system reactivity to pain in trigeminal neuralgia.

BACKGROUND: In the past two decades, there has been increasing evidence to suggest that trigeminal neuralgia (TN) may be linked to a dysfunction of the autonomic nervous system (ANS). The aim of the present study was to formally test this hypothesis by comparing the reactivity of the ANS to experimental pain in a population of TN patients and healthy controls. METHODS: Twelve patients diagnosed with classical TN and 12 healthy controls participated in the study. Cardiac activity was assessed while participants were instructed to rest and again during a cold pressor test (CPT). Heart rate variability analyses were performed off-line to obtain parasympathetic (high-frequency) and sympathetic (low-frequency) indices. RESULTS: At baseline, ANS measures did not differ between healthy controls and TN patients, and both groups showed a similar increase in heart rate during the CPT (all p values >0.05). However, TN patients showed a greater increase in cardiac sympathetic activity and a greater decrease in cardiac parasympathetic activity during CPT compared with healthy controls (all p values <0.05). Importantly, changes in sympathetic reactivity, from baseline to CPT, were negatively associated with the number of pain paroxysms experienced each day by TN patients in the preceding week (r=-.58, p<0.05). CONCLUSIONS: These results suggest that TN, like many other short-lasting, unilateral facial pain conditions, is linked to ANS alterations. Future studies are required to determine if the altered ANS response observed in TN patients is a cause or a consequence of TN pain.

Evaluation of the Bonapace Method: a specific educational intervention to reduce pain during childbirth.

OBJECTIVE: As pain during childbirth is very intense, several educational programs exist to help women prepare for the event. This study evaluates the efficacy of a specific pain management program, the Bonapace Method (BM), to reduce the perception of pain during childbirth. The BM involves the father, or a significant partner, in the use of several pain control techniques based on three neurophysiological pain modulation models: (1) controlling the central nervous system through breathing, relaxation, and cognitive structuring; (2) using non-painful stimuli as described in the Gate Control Theory; and (3) recruiting descending inhibition by hyperstimulation of acupressure trigger points. METHODS: A multicenter case control study in Quebec on pain perception during labor and delivery compared traditional childbirth training programs (TCTPs) and the BM. Visual analog scales were used to measure pain perception during labor. In all, 25 women (TCTP: n = 12; BM: n = 13) successfully reported their perceptions of pain intensity and unpleasantness every 15 minutes. RESULTS: A POSITIVE CORRELATION BETWEEN THE PROGRESSION OF LABOR AND PAIN WAS FOUND (PAIN INTENSITY: P < 0.01; pain unpleasantness: P < 0.01). When compared to TCTP, the BM showed an overall significant lower pain perception for both intensity (45%; P < 0.01) and unpleasantness (46%; P < 0.01). CONCLUSION: These significant differences in pain perception between TCTP and the BM suggest that the emphasis on pain modulation models and techniques during labor combined with the active participation of a partner in BM are important variables to be added to the traditional childbirth training programs for childbirth pain management.

Placebo and nocebo: how to enhance therapies and avoid unintended sabotage to pain treatment.

SUMMARY There is good evidence showing that placebo and nocebo responses do not only reflect a psychological reappraisal of an unchanged nociceptive activity. There are several scientific evidences indicating that placebo or nocebo responses trigger changes in the brain that activate descending modulatory mechanisms, affecting the nociceptive signal early in the CNS. Among the psychological factors that trigger a placebo or nocebo response, conditioning and expectation have been demonstrated to greatly affect the outcomes of pain perception, but also the response to treatment. Placebo or nocebo responses can be triggered without the administration of an inert substance in several therapeutic contexts and will affect the treatment outcome. In this article, we will describe different experimental situations where psychological factors produce physiological changes of the nociceptive signal in the brain, and how these changes are reflected in the spinal cord. Finally, we will discuss the importance of better understanding placebo and nocebo mechanisms in clinical contexts for pain treatment.

Pain inhibition is deficient in chronic widespread pain but normal in major depressive disorder.

BACKGROUND: Given the complex relationships between fibromyalgia and major depressive disorder (MDD), it has been suggested that fibromyalgia is a "masked" MDD. In experimental settings, fibromyalgia is associated with lowered pain thresholds (hyperalgesia) and deficient pain inhibition. Similarly, it has been recently proposed that the proneness of patients with MDD to develop chronic pain results from a deficit in pain inhibition. This cross-sectional study measured experimentally induced pain perception and inhibition in patients with MDD and patients with fibromyalgia. METHOD: Participants were 29 patients with fibromyalgia (American College of Rheumatology criteria), 26 patients with MDD (DSM-IV criteria), and 40 healthy controls who did not differ in age, sex, or the presence or absence of a menstrual cycle. Data were collected between June 2007 and May 2008. Thermal stimuli were used to measure pain thresholds. Pain inhibition was elicited using a tonic thermal test (Peltier thermode) administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold pressor test. RESULTS: Thermal pain thresholds were higher in healthy controls compared to patients with MDD and patients with fibromyalgia. Pain ratings during the cold pressor test were lower in healthy controls and patients with MDD relative to patients with fibromyalgia. Finally, DNIC efficacy was stronger in healthy controls compared to patients with fibromyalgia, while no significant differences were found between healthy controls and patients with MDD. CONCLUSIONS: Our results suggest that (1) fibromyalgia and MDD are both associated with signs of hyperalgesia, (2) hyperalgesia is more pronounced in fibromyalgia, and (3) the deficit of pain inhibition is specific to fibromyalgia. As such, these results suggest that there is an overlap between fibromyalgia and MDD, but that fibromyalgia can be distinguished from MDD in terms of DNIC efficacy.

No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls.

BACKGROUND: In animals, decades of research have shown that serotonin (5-HT) is involved in endogenous pain inhibition systems, which are deficient in chronic pain disorders such as fibromyalgia (FM). In humans, there is preliminary evidence showing that 5-HT is involved in the FM pathophysiology. In the current endophenotyping study, we sought to investigate, for the first time in humans, the relationships between the serotonin transporter promoter region (5-HTTLPR) polymorphism and experimentally-induced pain perception/inhibition in healthy controls (HC) and FM patients. METHODS: Participants were 58 FM patients and 60 HC, who did not differ in age, sex or menstrual cycle. Thermal stimuli were used to measure pain thresholds. Pain inhibition was elicited using a tonic thermal test (Peltier thermode) administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold-pressor test (CPT). RESULTS: Thermal pain thresholds were higher in HC compared to FM patients. Pain ratings during the CPT were lower in HC, relative to FM patients. Also, DNIC efficacy was stronger in HC compared to FM patients. However, there was no relationship between 5-HTTLPR and experimentally-induced pain perception/inhibition. DISCUSSION: Our results further confirm that FM is associated with thermal hyperalgesia and deficient DNIC. However, we found no evidence showing that the 5-HTTLPR polymorphism influences pain perception and DNIC. Potential reasons for this negative result will be discussed. Further endophenotyping studies of 5-HT-related gene polymorphisms are required to ascertain the potential relationships between 5-HT and human pain perception/inhibition.

DRD3 Ser9Gly polymorphism is related to thermal pain perception and modulation in chronic widespread pain patients and healthy controls.

UNLABELLED: Experimental studies showed that dopamine influences pain perception in healthy volunteers. Dopamine dysfunctions have been linked to the physiopathology of fibromyalgia (FM), which is associated with hyperalgesia and deficient pain inhibition. We sought to investigate the relationships between catecholamine-related polymorphisms [dopamine-D(3) receptor (DRD3) Ser9Gly and catechol-O-methyltransferase (COMT) Val158Met] and thermal pain measures in healthy subjects and FM patients. Seventy-three subjects (37 FM patients and 36 controls) participated in this study. Thermal pain thresholds (TPTs) were measured using a Peltier thermode. Inhibitory systems were elicited using a thermal tonic pain stimulation administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold-pressor test. Genetic analyses were performed using polymerase chain reaction. Regression analyses were performed across and within groups. FM was associated with lower TPTs and deficient pain inhibition. DRD3 Ser9Gly polymorphism predicted (1) DNIC efficacy across groups and (2) thermal TPTs in FM patients. COMT Val158Met and thermal pain measures were not related. These preliminary results suggest that the DRD3 Ser9Gly polymorphism influences DNIC efficacy and TPTs and that this latter relationship is present only in FM patients. Two core psychophysical features of FM appear to be significantly influenced by limbic dopamine functioning. PERSPECTIVE: This experimental study is the first to relate DNIC and TPTs to a functional polymorphism of limbic dopamine-D3 receptors. As lowered pain thresholds and deficient pain inhibition are 2 core features of fibromyalgia, these preliminary results may help identify a subgroup of FM patients who require closer medical attention.

Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses.

Several factors have been proposed to account for the differences observed between men and women in pain perception. One of these is female and male gonadal hormones. In order to verify this assumption, a hormone replacement (pellets inserted subcutaneously) of (1) 17beta-estradiol, (2) progesterone, (3) 17beta-estradiol + progesterone or (4) testosterone have been performed in gonadectomized female and male Sprague-Dawley rats. Twenty-one days after the hormonal replacement, a formalin test was performed. The nociceptive responses were divided in three distinct phases: acute (phase I), inhibitory (interphase) and tonic (phase II). After analysis, we observed that testosterone has a hypoalgesic effect on phases I and II of the formalin test. At the opposite, female hormones act only on the interphase: the combination of 17beta-estradiol and progesterone in gonadectomized rats reestablishes the weaker nociceptive pain reduction during the interphase as it is observed in the intact female. These effects were not gender specific since they had the same action in female and male. Our results permit to believe that testosterone plays a protective role in pain perception. Moreover, the female hormones act mainly on pain inhibition mechanisms (interphase), suggesting that the prevalence of certain chronic pain conditions in women could be related to a deficit of these pain inhibitory mechanisms rather than an increased nociceptive activity.

The role of sex hormones on formalin-induced nociceptive responses.

Many chronic pain conditions are more frequent in women than in men. This observation suggests that there is a potential role of sex hormones on pain perception. In the present study, we measured nociceptive responses to the formalin test in normal and gonadectomized male and female rats. The nociceptive responses to formalin injection were divided in four phases: acute (phase I), interphase and late phases (phases II and III). Four groups of rats were tested: (a) males (n = 15), (b) females (n = 16), (c) ovariectomized females (OVX) (n = 15) and (d) castrated males (CAST) (n = 15). Females presented significantly more nociceptive responses than males during phase I, interphase and phase II (P < 0.01). They also presented significantly more nociceptive responses than OVX females during the interphase (P < 0.05). CAST males presented significantly more nociceptive responses during the phases I (P < 0.01), II (P < 0.01) and III (P < 0.05) than the male rats. Finally, the responses of CAST males and OVX females were virtually identical, suggesting that the differences recorded between males and females in the formalin test were related to an activational effect of the sex hormones rather than an organizational effect. In conclusion, these results permit the support of the role of sex hormones on the modulation of pain perception. Interestingly, male and female sex hormones seem to act specifically on the different phases of the formalin test, suggesting some specific roles for sex hormones in different pain conditions.

Combined effect of xenoestrogens and growth factors in two estrogen-responsive cell lines.

It is now well recognized that estrogenic signaling mechanisms are far more complex than once thought. Several crosstalks between the estrogen receptor and other signaling pathways may influence the estrogenic stimulation of cell growth. Thus, the estrogenic effects of several environmental contaminants, now suspected to act as endocrine disrupters, may be influenced by a simultaneous stimulation of other signaling pathways. The aim of this study was to investigate whether the growth response of two estrogen-responsive cell lines, MCF-7 and GH3, treated with xenoestrogens might be affected by the addition of growth factors to their culture medium. Cells were treated with two known xenoestrogens, endosulfan and chlordane, alone or in the presence of insulin-like growth factor-1 and epidermal growth factor, respectively, and their growth was measured using the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxyanilide proliferation assay. Our results show that treatment with endosulfan or chlordane as well as treatment with growth factors increased cell growth, while the administration of xenoestrogens together with growth factors triggered a partly additive response with no antagonist or synergistic effect. These results sustain a role for xenoestrogens in cellular growth.