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Non-steroidal anti-inflammatory drugs, cyclo-oxygenase inhibitors, are used routinely in the treatment of primary headache disorders. Indomethacin is unique in its use in the diagnosis and treatment of hemicrania continua and paroxysmal hemicrania. The mechanism of this specific action is not fully understood, although an interaction with nitric oxide signaling pathways has been suggested. Trigeminovascular neurons were activated by dural electrical stimulation, systemic administration of a nitric oxide donor, or local microiontophoresis of L-glutamate. Using electrophysiological techniques, we subsequently recorded the activation of trigeminovascular neurons and their responses to intravenous indomethacin, naproxen and ibuprofen. Administration of indomethacin (5 mgkg), ibuprofen (30 mgkg) or naproxen (30 mgkg) inhibited dural-evoked firing within the trigeminocervical complex with different temporal profiles. Similarly, both indomethacin and naproxen inhibited L-glutamate-evoked cell firing suggesting a common action. In contrast, only indomethacin was able to inhibit nitric oxide-induced firing. The differences in profile of effect of indomethacin may be fundamental to its ability to treat paroxysmal hemicrania and hemicrania continua. The data implicate nitric oxide-related signaling as a potential therapeutic approach to these disorders.
Learn More >Chronic pain reduces life quality and is an important clinical problem associated with emotional and cognitive dysfunction. Epigenetic regulation of DNA methylation is involved in the induction of abnormal behaviors and pathological gene expression. We examined whether acupuncture can restore epigenetic changes caused by chronic pain, and identified the underlying mechanisms in neuropathic pain mice. Acupuncture treatment for 6 months (3 days/week) improved mechanical/cold allodynia and the emotional/cognitive dysfunction caused by left partial sciatic nerve ligation (PSNL)-induced neuropathic pain. The effects of acupuncture were associated with global DNA methylation recovery in the prefrontal cortex (PFC). Analysis of DNA methylation patterns in PFC indicated that 1,364 overlapping genes among 4,442 and 4,416 methylated genes in the PSNL vs. sham and PSNL vs. AP groups, respectively, were highly associated with the DNA methylation process. Acupuncture restored the reduced expression of 5-methylcytosine, methyl-CpG binding protein 2, and DNA methyltransferase family enzymes induced by PSNL in PFC. Methylation levels of Nr4a1 and Chkb associated with mitochondrial dysfunction were decreased in PFC of the PSNL mice, and increased by acupuncture. In contrast, high expression of Nr4a1 and Chkb mRNA in PSNL mice decreased after acupuncture. We also found that acupuncture inhibited the expression of Ras pathway-related genes such as Rasgrp1 and Rassf1. Finally, the expression of Nr4a1, Rasgrp1, Rassf1, and Chkb mRNA increased in the neuronal cells treated with Mecp2 siRNA. These results suggest that acupuncture can relieve chronic pain-induced comorbid conditions by altering DNA methylation of Nr4a1, Rasgrp1, Rassf1, and Chkb in the PFC.
Learn More >Spinal high mobility group box 1 protein (HMGB1) plays crucial roles in arthritis-induced pain, however the involvement of peripheral HMGB1 has not been examined previously. In this study, we addressed the role of peripheral HMGB1 and explored if sex contributes differentially to nociception in arthritis. We found Hmgb1 expression to be elevated in the ankle joints of male and female mice subjected to collagen antibody-induced arthritis (CAIA). Blocking the action of peripheral HMGB1, however, only reversed CAIA-induced hypersensitivity in males. Intra-articular injection of the toll-like receptor (TLR)4-activating, partially reduced disulfide, but not the fully reduced all-thiol, HMGB1 evoked mechanical hypersensitivity in both sexes. A sex-dependent temporal profile in expression of inflammatory factors in the ankle joint was observed in response to intra-articular injection of disulfide HMGB1, with male mice showing a delayed, yet longer lasting increase in mRNA levels for several of the investigated factors. Intra-articular HMGB1 did not induce cellular infiltration in the ankle joint suggesting its action on tissue resident cells. To further explore possible sex differences in cellular involvement, we used the macrophage inhibitor, minocycline, and mice with specific TLR4 depletion in myeloid cells or nociceptors. We found that inhibition of resident macrophages attenuated HMGB1-induced pain-like behavior only in male mice. Interestingly, while the contribution of TLR4 on myeloid cells to nociception was minimal in females compared to males, TLR4 on nociceptors are important for HMGB1-induced pain in both sexes. Collectively, our work highlights sex- and cellular location-dependent roles of HMGB1 and TLR4 in peripheral pain mechanisms.
Learn More >Innovation in the field of brain-machine interfacing offers a new approach to managing human pain. In principle, it should be possible to use brain activity to directly control a therapeutic intervention in an interactive, closed-loop manner. But this raises the question as to whether the brain activity changes as a function of this interaction. Here, we used real-time decoded functional MRI responses from the insula cortex as input into a closed-loop control system aimed at reducing pain and looked for co-adaptive neural and behavioral changes. As subjects engaged in active cognitive strategies orientated toward the control system, such as trying to enhance their brain activity, pain encoding in the insula was paradoxically degraded. From a mechanistic perspective, we found that cognitive engagement was accompanied by activation of the endogenous pain modulation system, manifested by the attentional modulation of pain ratings and enhanced pain responses in pregenual anterior cingulate cortex and periaqueductal gray. Further behavioral evidence of endogenous modulation was confirmed in a second experiment using an EEG-based closed-loop system. Overall, the results show that implementing brain-machine control systems for pain induces a parallel set of co-adaptive changes in the brain, and this can interfere with the brain signals and behavior under control. More generally, this illustrates a fundamental challenge of brain decoding applications-that the brain inherently adapts to being decoded, especially as a result of cognitive processes related to learning and cooperation. Understanding the nature of these co-adaptive processes informs strategies to mitigate or exploit them.
Learn More >Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets-nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABA) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the -terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.
Learn More >The differentiation of chronic primary pain syndromes into those with widespread versus regional musculoskeletal pain has been characterized by controversial discussions about common or distinct mechanisms and core clinical and sensory criteria. For example, the recent revision of fibromyalgia criteria has discarded sensory characteristics such as number of "tender points". This study examined empirical evidence related to this diagnostic shift and aimed to identify basic sensory-clinical pain phenotypes in patients with chronic local primary pain (chronic primary back pain, CBP) and patients with chronic widespread primary pain (fibromyalgia syndrome, FMS). Combined sensory-clinical pain phenotypes of 185 patients with prior CBP and FMS diagnoses were derived by a stepwise data-reduction through descriptive statistical, correlational, principal components and latent class analyses. Clusters were cross-validated by linear discriminant analysis. Four clusters of patients were identified, requiring four pressure pain sensitivity markers (number of sensitive tender and control points, pain intensity and pressure pain threshold at the trapezius) and two clinical pain characteristics (pain regions, present pain intensity). Subsequent discriminant analysis revealed that three discriminant functions of pressure sensitivity markers sufficed to differentiate the clusters. These sensory-clinical phenotypes differed also in somatic symptoms and impairment but neither in psychopathology nor in psychosocial co-factors. The results highlight the relevance of sensory testing in combination with clinical pain assessment in chronic primary pain syndromes.
Learn More >Pain after total knee arthroplasty (TKA) is a prevalent condition. This study compared the effectiveness of tapentadol extended release (ER) 50 mg x 2, oxycodone controlled release (CR) 10 mg x 2 and placebo; as added to a multimodal analgesic regime both in-hospital and at home the first week after TKA. The study was randomized and blinded for investigators, staff, outcome assessors and patients. Follow-up included pain intensity on mobilization, pain at rest, worst pain in the previous 24 hours, and adverse effects measured on 0-10 numeric rate scales. A total of 134 patients in three study groups received their allocated intervention and were included in the analysis. The primary outcome pain on mobilization the 7 first postoperative days reported as mean pain Area Under the Curve (AUC) was 528.1 (SD 267.5, IQR 356.6 to 665.4) for placebo, 427.2 (SD 203.9, IQR 303.6 to 544.3) for tapentadol ER and 507.9 (SD 243.7, IQR 292.4 to 686.8) for oxycodone CR (p=0.12). With the exception of constipation being less prevalent in the tapentadol ER group (p=0.02), we found no significant differences between treatment groups for the secondary outcomes. Tapentadol ER as an add-on to multimodal analgesia did not significantly improve pain relief when compared to oxycodone CR or placebo. Constipation was lowest in the tapentadol ER group.
Learn More >Adaptations in brain communication are associated with multiple pain disorders and are hypothesized to promote the transition from acute to chronic pain. Despite known increases in brain synaptic activity, it is unknown if and how changes in pathways and networks contribute to persistent pain. A tunable rat model that induces transient or persistent temporomandibular joint pain was used to characterize brain network and sub-circuit changes when sensitivity is detected in both transient and persistent pain groups and later when sensitivity is present only for the persistent pain group. Brain activity was measured by F-FDG PET imaging and used to construct inter-subject correlation networks; network connectivity distributions, diagnostics, and community structure were assessed. Activation of sub-circuits was tested by structural equation modeling. Findings reveal differences in the brain networks at day 7 between the persistent and transient pain groups, a time when peripheral sensitivity is detected in both groups, but spontaneous pain occurs only in the persistent pain group. At day 7, increased (p≤0.01) clustering, node strength, network segregation, and activation of prefrontal-limbic pathways are observed only in the group that develops persistent pain. Later, increased clustering and node strength are more pronounced with persistent pain, particularly within the limbic system, and decrease when pain resolves. Pre-treatment with intraarticular etanercept to attenuate pain confirms these adaptations are associated with pain onset. Results suggest that early and sustained brain changes can differentiate persistent and transient pain, implying they could be useful as prognostic biomarkers for persistent pain and in identifying therapeutic targets.
Learn More >Cognitive behavioral therapy (CBT) is a psychological intervention that involves development of coping strategies to reduce the experience of pain. Although CBT is a promising intervention to reduce headache days in patients with migraine, it may not be effective for all patients. Thus, there is a need to identify markers that could predict which patients will respond to CBT. We aimed to determine if baseline brain function and amygdalar connectivity, assessed by fMRI, or pain modulation capacities, assessed by the conditioned pain modulation (CPM) response, can predict a reduction in headache days after CBT in adolescents with migraine. Patients with migraine (n = 20; age range 10-17 years) completed 8 weekly CBT sessions. The CPM response was examined in the trapezius and the leg. Headache days significantly decreased after CBT (p<0.001). Greater functional connectivity before CBT between the right amygdala and frontal gyrus, anterior cingulate cortex, and precentral gyrus was related to greater headache reduction after CBT. Greater reduction in headache days after CBT was related with less efficient CPM response before CBT at the trapezius (r=-0.492, p=0.028) but not at the leg. This study found that headache reduction after CBT was related to right amygdala connectivity with frontal and sensorimotor regions at baseline as well as baseline pain modulation capacities. These findings suggest that individual differences in brain function and pain modulation can be associated with clinical improvements and help with determination of CBT responsiveness.
Learn More >Adolescent idiopathic scoliosis is one of the most common spinal deformities in children and adolescents requiring extensive surgical intervention. Due to the nature of surgery, spinal fusion increases their risk of experiencing persistent postsurgical pain. Up to 20% of adolescents report pain for months or years after corrective spinal fusion surgery.
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