Steven E. Harte

Reduced insular γ-aminobutyric acid in fibromyalgia

OBJECTIVE Recent scientific findings have reinvigorated interest in examining the role of γ-aminobutyric acid (GABA), the major inhibitory central nervous system neurotransmitter, in chronic pain conditions. Decreased inhibitory neurotransmission is a proposed mechanism in the pathophysiology of chronic pain syndromes such as fibromyalgia (FM). The purpose of this study was to test the hypothesis that decreased levels of insular and anterior cingulate GABA would be present in FM patients, and that the concentration of this neurotransmitter would be correlated with pressure-pain thresholds. METHODS Sixteen FM patients and 17 age- and sex-matched healthy controls underwent pressure-pain testing and a 3T proton magnetic resonance spectroscopy session in which the right anterior insula, right posterior insula, anterior cingulate, and occipital cortex were examined in subjects at rest. RESULTS GABA levels in the right anterior insula were significantly lower in FM patients compared with healthy controls (mean ± SD 1.17 ± 0.24 arbitrary institutional units versus 1.42 ± 0.32 arbitrary institutional units; P = 0.016). There was a trend toward increased GABA levels in the anterior cingulate of FM patients compared with healthy controls (P = 0.06). No significant differences between groups were detected in the posterior insula or occipital cortex (P > 0.05 for all comparisons). Within the right posterior insula, higher levels of GABA were positively correlated with pressure-pain thresholds in the FM patients (Spearmans rho = 0.63; P = 0.02). CONCLUSION Diminished inhibitory neurotransmission resulting from lower concentrations of GABA within the right anterior insula may play a role in the pathophysiology of FM and other central pain syndromes.

Resting state connectivity correlates with drug and placebo response in fibromyalgia patients

Fibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response. We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition. 15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex. This study indicates that ACC–IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response.

Increased Pressure Pain Sensitivity in Women With Chronic Pelvic Pain

OBJECTIVE: To determine whether women with chronic pelvic pain and variable degrees of endometriosis demonstrate altered pain sensitivity relative to pain-free healthy women in a control group and whether such differences are related to the presence or severity of endometriosis or comorbid pain syndromes. METHODS: Four patient subgroups (endometriosis with chronic pelvic pain [n=42], endometriosis with dysmenorrhea [n=15], pain-free endometriosis [n=35], and chronic pelvic pain without endometriosis [n=22]) were each compared with 30 healthy women in a control group in this cross-sectional study. All patients completed validated questionnaires regarding pain symptoms and underwent screening for comorbid pain disorders. Pain sensitivity was assessed by applying discrete pressure stimuli to the thumbnail using a previously validated protocol. RESULTS: While adjusting for age and education, pain thresholds were lower in all subgroups of women with pelvic pain relative to healthy women in the control group (all P values <.01). There was no difference in pain thresholds when comparing patients with endometriosis without pelvic pain with healthy women in the control group (mean difference 0.02 kg/m2, 95% confidence interval −0.43 to 0.47). The presence and severity of endometriosis and number of comorbid pain syndromes were not associated with a difference in pain thresholds. CONCLUSION: Women with chronic pelvic pain demonstrate increased pain sensitivity at a nonpelvic site compared with healthy women in a control group, which is independent of the presence or severity of endometriosis or comorbid pain syndromes. These findings support the notion that central pain amplification may play a role in the development of pelvic pain and may explain why some women with pelvic pain do not respond to therapies aimed at eliminating endometriosis lesions. LEVEL OF EVIDENCE: II

Herpes simplex virus vector-mediated expression of interleukin-10 reduces below-level central neuropathic pain after spinal cord injury

Background. Neuroimmune activation in the spinal dorsal horn plays an important role in the pathogenesis of chronic pain after peripheral nerve injury. Objective. The aim of this study was to examine the role of neuroimmune activation in below-level neuropathic pain after traumatic spinal cord injury (SCI). Methods. Right hemilateral SCI was created in male Sprague–Dawley rats by controlled blunt impact through a T12 laminectomy. Pain-related behaviors were assessed using both evoked reflex responses and an operant conflict-avoidance test. Neuroimmune activation was blocked by the anti-inflammatory cytokine interleukin-10 (IL-10) delivered by a nonreplicating herpes simplex virus (HSV)–based gene transfer vector (vIL10). Markers of neuroimmune activation were assessed using immunohistochemistry and Western blot. Results. One week after SCI, injured animals demonstrated mechanical allodynia, thermal hyperalgesia, and mechanical hyperalgesia in the hind limbs below the level of injury. Animals inoculated with vIL10 had a statistically significant reduction in all of these measures compared to injured rats or injured rats inoculated with control vector. Conflict-avoidance behavior of injured rats inoculated with vIL10 was consistent with significantly reduced pain compared with injured rats injected with control vector. These behavioral results correlated with a significant decrease in spinal tumor necrosis factor α (mTNFα) expression assessed by Western blot and astrocyte activation assessed by glial fibrillary acidic protein immunohistochemistry. Conclusion. Below-level pain after SCI is characterized by neuroimmune activation (increase mTNFα and astrocyte activation). Blunting of the neuroimmune response by HSV-mediated delivery of IL-10 reduced pain-related behaviors, and may represent a potential novel therapeutic agent.

Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy.

Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor‐positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment‐related toxicities like musculoskeletal pain. Although pain‐related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation.

Pain is associated with short leukocyte telomere length in women with fibromyalgia

UNLABELLED Telomere length, considered a measure of biological aging, is linked to morbidity and mortality. Psychosocial factors associated with shortened telomeres are also common in chronic pain; yet, little is known about telomere length in pain populations. Leukocyte telomere length was evaluated in 66 women with fibromyalgia and 22 healthy female controls. Participants completed questionnaires and a subgroup of fibromyalgia patients underwent quantitative sensory testing (QST; n = 12) and neuroimaging (n = 12). Telomere length was measured using the quantitative polymerase chain reaction method. Although patients had shorter telomere length than controls, the difference was not statistically significant. However, higher levels of pain within fibromyalgia were associated with shorter telomere length (P = .039). When pain and depression were combined, patients categorized as high-pain/high-depression had an age-adjusted telomere length 265 base pairs shorter than those with low-pain/low-depression (P = .043), a difference consistent with approximately 6 years of chronological aging. In the subset tested, telomere length was also related to pain threshold and pain sensitivity, as well as gray matter volume, such that patients with shorter telomeres were more sensitive to evoked pain and had less gray matter in brain regions associated with pain processing (eg, primary somatosensory cortex). These preliminary data support a relationship between pain and telomere length. PERSPECTIVE Our findings support a link between premature cellular aging and chronic pain. These preliminary data imply that chronic pain is a more serious condition than has typically been recognized in terms of bodily aging.

Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy

Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor‐positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment‐related toxicities like musculoskeletal pain. Although pain‐related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation.

Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study.

Abstract Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia (FM), but it is unknown if this dysfunction is related to established neurobiological markers of hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in patients with FM as compared with healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging with endogenous MOR binding and clinical pain ratings in female opioid-naive patients with FM (n = 18) using whole-brain analyses and regions of interest from our previous research. Within antinociceptive brain regions, including the dorsolateral prefrontal cortex (r = 0.81, P < 0.001) and multiple regions of the anterior cingulate cortex (all r > 0.67; all P < 0.02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, P = 0.050). In many of these regions, pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggest that dysregulation of the endogenous opioid system in FM could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in FM.

Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study

BACKGROUND Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition characterized by pelvic pain and urinary symptoms. Some IC/BPS patients have pain confined to the pelvic region, while others suffer widespread pain. Inflammatory processes have previously been linked to pelvic pain in IC/BPS, but their association with widespread pain in IC/BPS has not been characterized. METHODS Sixty-six women meeting criteria for IC/BPS completed self-report measures of pain as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP), collected 3days of saliva for cortisol assays, and provided blood samples. Peripheral blood mononuclear cells (PBMCs) were stimulated with Toll-like Receptor (TLR) 2 and 4 agonists and cytokines were measured in supernatant; IL-6 was also measured in plasma. Associations between inflammatory variables and the likelihood of endorsing extra-pelvic pain, or the presence of a comorbid syndrome, were tested by logistic regression and General Linear Models, respectively. A subset of patients (n=32) completed Quantitative Sensory Testing. RESULTS A one standard deviation increase in TLR-4 inflammatory response was associated with a 1.59 greater likelihood of endorsing extra-pelvic pain (p=.019). Participants with comorbid syndromes also had higher inflammatory responses to TLR-4 stimulation in PBMCs (p=.016). Lower pressure pain thresholds were marginally associated with higher TLR-4 inflammatory responses (p=.062), and significantly associated with higher IL-6 in plasma (p=.031). CONCLUSIONS TLR-4 inflammatory responses in PBMCs are a marker of widespread pain in IC/BPS, and should be explored in other conditions characterized by medically unexplained pain.

Functional Interaction between Medial Thalamus and Rostral Anterior Cingulate Cortex in the Suppression of Pain Affect

The medial thalamic parafascicular nucleus (PF) and the rostral anterior cingulate cortex (rACC) are implicated in the processing and suppression of the affective dimension of pain. The present study evaluated the functional interaction between PF and rACC in mediating the suppression of pain affect in rats following administration of morphine or carbachol (acetylcholine agonist) into PF. Vocalizations that occur following a brief noxious tailshock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed by injection of morphine or carbachol into PF. Vocalizations that occur during tailshock were suppressed to a lesser degree, whereas, spinal motor reflexes (tail flick and hindlimb movements) were only slightly suppressed by injection of carbachol into PF and unaffected by injection of morphine into PF. Blocking glutamate receptors in rACC (NMDA and non-NMDA) by injecting D-2-amino-5-phosphonovalerate (AP-5) or 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) produced dose-dependent antagonism of morphine-induced increases in vocalization thresholds. Carbachol-induced increases in vocalization thresholds were not affected by injection of either glutamate receptor antagonist into rACC. The results demonstrate that glutamate receptors in the rACC contribute to the suppression of pain affect produced by injection of morphine into PF, but not to the suppression of pain affect generated by intra-PF injection of carbachol.