Thalamic neurometabolite alterations in chronic low back pain: a common phenomenon across musculoskeletal pain conditions?

ABSTRACT: Recently, we showed that patients with knee osteoarthritis (KOA) demonstrate alterations in the thalamic concentrations of several metabolites compared with healthy controls: higher myo-inositol (mIns), lower N-acetylaspartate (NAA), and lower choline (Cho). Here, we evaluated whether these metabolite alterations are specific to KOA or could also be observed in patients with a different musculoskeletal condition, such as chronic low back pain (cLBP). Thirty-six patients with cLBP and 20 healthy controls were scanned using 1 H-magnetic resonance spectroscopy (MRS) and a PRESS (Point RESolved Spectroscopy) sequence with voxel placement in the left thalamus. Compared with healthy controls, patients with cLBP demonstrated lower absolute concentrations of NAA ( P = 0.0005) and Cho ( P < 0.05) and higher absolute concentrations of mIns ( P = 0.01) when controlling for age, as predicted by our previous work in KOA. In contrast to our KOA study, mIns levels in this population did not significantly correlate with pain measures (eg, pain severity or duration). However, exploratory analyses revealed that NAA levels in patients were negatively correlated with the severity of sleep disturbance ( P < 0.01), which was higher in patients compared with healthy controls ( P < 0.001). Additionally, also in patients, both Cho and mIns levels were positively correlated with age ( P < 0.01 and P < 0.05, respectively). Altogether, these results suggest that thalamic metabolite changes may be common across etiologically different musculoskeletal chronic pain conditions, including cLBP and KOA, and may relate to symptoms often comorbid with chronic pain, such as sleep disturbance. The functional and clinical significance of these brain changes remains to be fully understood.

Stomatin-like protein 3 modulates the responses of Aδ, but not C fiber bone afferent neurons to noxious mechanical stimulation in an animal model of acute experimental bone pain.

STOML3 is a membrane bound scaffolding protein that has been shown to facilitate the opening of mechanically sensitive ion channels and contribute to noxious mechanical sensation, allodynia and hyperalgesia. In this study, we aimed to determine the role of STOML3 in noxious mechanical sensitivity of bone afferent neurons and carrageenan-induced acute inflammation in the bone. An in vivo, electrophysiological bone-nerve preparation was used to make recordings of the activity and sensitivity of bone afferent neurons that innervate the tibial marrow cavity in anaesthetised rats, in response to noxious mechanical stimuli delivered to the marrow cavity, before and after injection of either the STOML3 oligomerisation inhibitor OB-1 or vehicle, in either naïve animals or animals with carrageenan-induced inflammation of the marrow cavity. A dynamic weight-bearing apparatus was used to measure weight bearing in response to inflammatory pain before and after injection of OB-1 or saline into the tibial marrow cavity in the presence of carrageenan-induced inflammation. Electrophysiological recordings revealed that Aδ, but not C bone afferent neurons have a reduced discharge frequency in response to mechanical stimulation, and that carrageenan-induced sensitisation of Aδ, but not C bone afferent neurons was attenuated by inhibition of STOML3 oligomerisation with OB-1. Animals treated with OB-1 spent a significantly greater amount of time on the limb injected with carrageenan than animals treated with saline. Our findings demonstrate that inhibition of STOML3 oligomerisation reduces inflammatory bone pain by reducing the sensitivity of Aδ bone afferent neurons to mechanical stimulation. Targeting STOML3 may be an effective approach to reduce pain from noxious pressure and/or painful inflammatory pathology in bone.

The Role of TNF-α in the Pathogenesis of Temporomandibular Disorders.

Temporomandibular disorder (TMD) is an oral dentofacial disease that is related to multiple factors such as disordered dental occlusion, emotional stress, and immune responses. In the past decades, tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, has provided valuable insight into the pathogenesis of TMD, particularly in settings associated with inflammation. It is thought that TNF-α participates in the pathogenesis of TMD by triggering immune responses, deteriorating bone and cartilage, and mediating pain in the temporomandibular joint (TMJ). Initially, TNF-α plays the role of "master regulator" in the complex immune network by increasing or decreasing the production of other inflammatory cytokines. Then, the effects of TNF-α on cells, particularly on chondrocytes and synovial fibroblasts, result in pathologic cartilage degradation in TMD. Additionally, multiple downstream cytokines induced by TNF-α and neuropeptides can regulate central sensitization and inflammatory pain in TMD. Previous studies have also found some therapies target TMD by reducing the production of TNF-α or blocking TNF-α-induced pathways. All this evidence highlights the numerous associations between TNF-α and TMD; however, they are currently not fully understood and further investigations are still required for specific mechanisms and treatments targeting specific pathways. Therefore, in this review, we explored general mechanisms of TNF-α, with a focus on molecules in TNF-α-mediated pathways and their potential roles in TMD treatment. In view of the high clinical prevalence rate of TMD and damage to patients' QOL, this review provides adequate evidence for studying links between inflammation and TMD in further research and investigation.

Effects of Nutritional Interventions in the Control of Musculoskeletal Pain: An Integrative Review.

Food consumption has significant positive effects on an individual's health status, including the reduction of symptoms associated with musculoskeletal pain. However, specific food groups indicated for the treatment of pain are not yet determined. Hence, this review aimed to analyze the effects of nutritional interventions with specific diets, oils and/or fatty acids, and foodstuffs in natura in the reduction of musculoskeletal pain. An integrative review was conducted in the following databases: Embase, PubMed, LILACS, and Google Scholar. Clinical trials written in English, Spanish, and Portuguese and published between 2000 and March 2020 were included in this review. Seventeen studies were included. Among these, a reduction of musculoskeletal pain with different types of nutritional interventions, such as vegan and Mediterranean diets and the consumption of blueberry, strawberry, passion fruit peel extract, argan oil, fish oil (omega-3), olive oil, and undenatured type II collagen and vitamin D gel capsules, was observed in 14 studies. Eight studies evaluated the profiles of several inflammatory markers, and of these, decreased interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α levels were observed in two studies. This review suggests that different nutritional interventions with specific diets, oils and/or fatty acids, and foodstuffs in natura reduce musculoskeletal pain, specifically in adults with osteoarthritis. Besides pain improvement, nutritional interventions, including the consumption of strawberry and vitamin D gel capsules, decrease the levels of several inflammatory markers.

Characterisation of nociception and inflammation observed in a traumatic muscle injury model in rats.

Muscle pain is the most prevalent type of pain in the world, but treatment remains ineffective. Thus, it is relevant to develop trustable animal models to understand the involved pain mechanisms. Therefore, this study characterised the nociception and inflammation in a traumatic muscle injury model in rats. A single blunt trauma impact on the right gastrocnemius muscle of male Wistar rats (250-350 g) was used as model for muscle pain. Animals were divided into four groups (sham/no treatment; sham/diclofenac 1%; injury/no treatment; injury/diclofenac 1%) and the topical treatment with a cream containing 1% monosodium diclofenac (applied at 2, 6, 12, 24, and 46 h after muscle injury; 200 mg/muscle) was used as an anti-inflammatory control. Nociception (mechanical and cold allodynia, or nociceptive score) and locomotor activity were evaluated at 26 and 48 h after injury. Also, inflammatory and oxidative parameters were evaluated in gastrocnemius muscle and the creatine kinase (CK) activity and lactate/glicose levels in rat's serum and plasma, respectively. Muscle injury caused mechanical and cold allodynia, and increased nociceptive scores, without inducing locomotor impairment. This model also increased the inflammatory cells infiltration (seen by myeloperoxidase and N-acetyl-ß-D-glucosaminidase activities and histological procedure), nitric oxide, interleukin (IL)-1ß, IL-6, and dichlorofluorescein fluorescence in muscle samples; and CK activity and lactate/glicose ratio. The treatment with 1% monosodium diclofenac reduced inflammatory cells infiltration, dichlorofluorescein fluorescence and lactate/glicose levels. Thus, we characterised the traumatic muscle injury as a reproducible model of muscle pain, which makes it possible to evaluate promising antinociceptive and anti-inflammatory therapies.

Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.

BACKGROUND: A proposed mechanism of chronic pain is dysregulation between the main inhibitory (GABA) and excitatory (glutamate) neurometabolites of the central nervous system. The level of these neurometabolites appears to differ in individual studies of people with pain compared to pain-free controls across different pain conditions. However, this has yet to be systematically investigated. AIMS: To establish whether GABA, glutamate, glutamine and Glx levels differ across pain conditions when compared to pain-free controls. METHODS: Five databases were searched. Studies were included if they investigated: 1) A pain condition compared to control. 2) Reported GABA, glutamate, glutamine or glutamate/glutamine level. 3) Used 1H-Magnetic Resonance Spectroscopy (Prospero Project ID CRD42018092170). Data extracted included neurometabolite level, pain diagnosis, and spectroscopy parameters. Meta-analyses were conducted to establish the difference in neurometabolite level between participants with pain and pain-free controls for different pain conditions. The MRS-Q was developed from existing clinical consensus to allow for the assessment of quality in the included studies. RESULTS: Thirty-five studies were included investigating combinations of migraine (n = 11), musculoskeletal pain (n = 8), chronic pain syndromes (n = 9) and miscellaneous pain (n = 10). Higher GABA levels were found in participants with migraine compared to controls (Hedge's G 0.499, 95%CI: 0.2 to 0.798). In contrast, GABA levels in musculoskeletal pain conditions (Hedge's G -0.189, 95%CI: 0.530 to 0.153) and chronic pain syndromes (Hedge's G 0.077, 95%CI: 1.612 to 1.459) did not differ from controls. Results for other brain neurometabolites revealed significantly higher levels for glutamate in participants with migraine and Glx in chronic pain syndromes compared to controls. CONCLUSION: These results support the theory that underlying neurometabolite levels may be unique in different pain conditions and therefore representative of biomarkers for specific pain conditions.

Tapentadol prolonged release in the treatment of musculoskeletal pain: an innovative pharmacological option.

Musculoskeletal pain, encompassing back and osteoarthritis (OA) pain, represents the most frequent source of chronic pain in western countries, and it is particularly frequent in older adults. Remarkably, back and OA pain present, in most cases, both a nociceptive and a neuropathic component of pain. Treatment selection should, therefore, properly consider the ability of a drug to act on both components, reducing the possibility of plastic changes in the central nervous system, and consequently promoting physical rehabilitation. The pharmacological profile of tapentadol, combining synergistically µ-opioid receptor (MOR) agonist and norepinephrine reuptake inhibition (NRI) in one single molecule with a concomitant reduction in the burden of adverse events, is unique, to date, and makes this drug particularly suitable for the treatment of back pain and OA-associated pain, especially when a neuropathic component is present. Tapentadol is an innovative dual-acting analgesic molecule, which combines two mechanisms of action, namely MOR agonism and NRI. This narrative review will briefly discuss the pharmacological action of tapentadol and its rationale for use in back pain and OA.

Pharmacological inhibition of the NLRP3 inflammasome as a potential target for cancer-induced bone pain.

Cancer-induced bone pain (CIBP) remains a major challenge in patients suffering from bone metastases because of the complex mechanisms and unsatisfactory treatments. Emerging evidence have shown that activation of inflammasomes contribute to the development of inflammatory and neuropathic pain. However, the role of spinal inflammasomes in CIBP remains unclear. In the present study, we explored the specific cellular mechanisms of NLRP3 inflammasome in the process of CIBP in rats. MCC950 is a small molecule inhibitor of the NLRP3 inflammasome that exhibits remarkable activity in inflammatory diseases. Our behavioral results confirmed that both single and persistent treatment with MCC950 markedly attenuated CIBP-related mechanical allodynia. The expression of NLRP3 inflammasome, including NLRP3, ASC, Caspase-1, were significantly increased in a time-dependent manner. Furthermore, spinal IL-1ß, cleaved by cysteine-aspartic acid protease, was upregulated in this study. Chronic administration with MCC950 restored the protein expression of NLRP3 inflammasome and significantly suppressed the upregulation of IL-1ß. Spinal NLRP3 inflammasome might be a novel therapeutic target for treatment of CIBP.

Interleukin 6 decreases nociceptor expression of the potassium channel KV1.4 in a rat model of hand-arm vibration syndrome.

Chronic muscle pain is a prominent symptom of the hand-arm vibration syndrome (HAVS), an occupational disease induced by exposure to vibrating power tools, but the underlying mechanism remains unknown. We evaluated the hypothesis that vibration induces an interleukin 6 (IL-6)-mediated downregulation of the potassium voltage-gated channel subfamily A member 4 (KV1.4) in nociceptors leading to muscle pain. Adult male rats were submitted to a protocol of mechanical vibration of the right hind limb. Twenty-four hours after vibration, muscle hyperalgesia was observed, concomitant to increased levels of IL-6 in the gastrocnemius muscle and decreased expression of KV1.4 in the dorsal root ganglia. Local injection of neutralizing antibodies against IL-6 attenuated the muscle hyperalgesia induced by vibration, whereas antisense knockdown of this channel in the dorsal root ganglia mimicked the muscle hyperalgesia observed in the model of HAVS. Finally, knockdown of the IL-6 receptor signaling subunit glycoprotein 130 (gp130) attenuated both vibration-induced muscle hyperalgesia and downregulation of KV1.4. These results support the hypothesis that IL-6 plays a central role in the induction of muscle pain in HAVS. This likely occurs through intracellular signaling downstream to the IL-6 receptor subunit gp130, which decreases the expression of KV1.4 in nociceptors.

Role of the purinergic P2X receptors in osteoclast pathophysiology.

Osteoclasts are cells of the hematopoietic lineage that are responsible for bone resorption. Their activity is crucial in the initiation of bone remodeling and for maintenance of a strong and healthy skeleton. However, in a number of diseases, including inflammatory disorders, inappropriately high osteoclast activity results in excessive bone degradation, bone loss, and subsequently fractures. A range of P2X purinergic receptors are expressed in bone cells, and osteoclasts express most of the P2X receptors. However, until recently only the role of the P2X7 receptor subtype in normal and pathophysiologic bone metabolism was documented while very few studies addressed the role of the remaining six P2X receptor subtypes. Recently, studies have documented that the P2X5 receptor not only controls osteoclastic bone resorption but also mediates inflammation-induced bone loss, while P2X2/3 receptors have dual functions in bone, both regulating bone resorption and mediating bone pain. Finally, an in vivo study showed that reduced P2X7 receptor function aggravates estrogen-withdrawal-induced bone loss, which is in line with the growing number of reports cementing the association between P2X7 receptor polymorphisms and development of osteoporosis and fracture risk. The studies reviewed in this article provide intriguing results highlighting the potential of P2X receptors as promising pharmaceutical targets in the treatment of bone loss associated with inflammatory (and other) diseases.

Involvement of Substance P in the Analgesic Effect of Low-Level Laser Therapy in a Mouse Model of Chronic Widespread Muscle Pain.

BACKGROUND: Low-level laser therapy (LLLT) is widely used in pain control in the field of physical medicine and rehabilitation and is effective for fibromyalgia pain. However, its analgesic mechanism remains unknown. A possible mechanism for the effect of LLLT on fibromyalgia pain is via the antinociceptive signaling of substance P in muscle nociceptors, although the neuropeptide has been known as a neurotransmitter to facilitate pain signals in the spinal cord. OBJECTIVE: To establish an animal model of LLLT in chronic muscle pain and to determine the role of substance P in LLLT analgesia. METHODS: We employed the acid-induced chronic muscle pain model, a fibromyalgia model proposed and developed by Sluka et al., and determined the optimal LLLT dosage. RESULTS: LLLT with 685 nm at 8 J/cm2 was effective to reduce mechanical hyperalgesia in the chronic muscle pain model. The analgesic effect was abolished by pretreatment of NK1 receptor antagonist RP-67580. Likewise, LLLT showed no analgesic effect on Tac1-/- mice, in which the gene encoding substance P was deleted. Besides, pretreatment with the TRPV1 receptor antagonist capsazepine, but not the ASIC3 antagonist APETx2, blocked the LLLT analgesic effect. CONCLUSIONS: LLLT analgesia is mediated by the antinociceptive signaling of intramuscular substance P and is associated with TRPV1 activation in a mouse model of fibromyalgia or chronic muscle pain. The study results could provide new insight regarding the effect of LLLT in other types of chronic pain.

Using a Consensus Docking Approach to Predict Adverse Drug Reactions in Combination Drug Therapies for Gulf War Illness.

Gulf War Illness (GWI) is a chronic multisymptom illness characterized by fatigue, musculoskeletal pain, and gastrointestinal and cognitive dysfunction believed to stem from chemical exposures during the 1990⁻1991 Persian Gulf War. There are currently no treatments; however, previous studies have predicted a putative multi-intervention treatment composed of inhibiting Th1 immune cytokines followed by inhibition of the glucocorticoid receptor (GCR) to treat GWI. These predictions suggest the use of specific monoclonal antibodies or suramin to target interleukin-2 and tumor necrosis factor α , followed by mifepristone to inhibit the GCR. In addition to this putative treatment strategy, there exist a variety of medications that target GWI symptomatology. As pharmaceuticals are promiscuous molecules, binding to multiple sites beyond their intended targets, leading to off-target interactions, it is key to ensure that none of these medications interfere with the proposed treatment avenue. Here, we used the drug docking programs AutoDock 4.2, AutoDock Vina, and Schrödinger's Glide to assess the potential off-target immune and hormone interactions of 43 FDA-approved drugs commonly used to treat GWI symptoms in order to determine their putative polypharmacology and minimize adverse drug effects in a combined pharmaceutical treatment. Several of these FDA-approved drugs were predicted to be novel binders of immune and hormonal targets, suggesting caution for their use in the proposed GWI treatment strategy symptoms.

Multi-OMICS analyses of frailty and chronic widespread musculoskeletal pain suggest involvement of shared neurological pathways.

Chronic widespread musculoskeletal pain (CWP) and frailty are prevalent conditions in older people. We have shown previously that interindividual variation in frailty and CWP is genetically determined. We also reported an association of frailty and CWP caused by shared genetic and common environmental factors. The aim of this study was to use omic approaches to identify molecular genetic factors underlying the heritability of frailty and its genetic correlation with CWP. Frailty was quantified through the Rockwood Frailty Index (FI) as a proportion of deficits from 33 binary health deficit questions in 3626 female twins. Common widespread pain was assessed using a screening questionnaire. OMICS analysis included 305 metabolites and whole-genome (>2.5 × 10 SNPs) and epigenome (∼1 × 10 MeDIP-seq regions) assessments performed on fasting blood samples. Using family-based statistical analyses, including path analysis, we examined how FI scores were related to molecular genetic factors and to CWP, taking into account known risk factors such as fat mass and smoking. Frailty Index was significantly correlated with 51 metabolites after correction for multiple testing, with 20 metabolites having P-values between 2.1 × 10 and 4.0 × 10. Three metabolites (uridine, C-glycosyl tryptophan, and N-acetyl glycine) were statistically independent and thought to exert a direct effect on FI. Epiandrosterone sulphate, previously shown to be highly inversely associated with CWP, was found to exert an indirect influence on FI. Bioinformatics analysis of genome-wide association study and EWAS showed that FI and its covariation with CWP was through genomic regions involved in neurological pathways. Neurological pathway involvement accounts for the associated conditions of aging CWP and FI.

A Functional riboSNitch in the 3' Untranslated Region of FKBP5 Alters MicroRNA-320a Binding Efficiency and Mediates Vulnerability to Chronic Post-Traumatic Pain.

Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene-miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies.SIGNIFICANCE STATEMENTFKBP5 is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3'UTR of FKBP5 that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the FKBP5 rs3800373 minor allele alters the secondary structure of FKBP5 mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater FKBP5 translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.

Neuropeptide Y is Up-regulated and Induces Antinociception in Cancer-induced Bone Pain.

Pain remains a major concern in patients suffering from metastatic cancer to the bone and more knowledge of the condition, as well as novel treatment avenues, are called for. Neuropeptide Y (NPY) is a highly conserved peptide that appears to play a central role in nociceptive signaling in inflammatory and neuropathic pain. However, little is known about the peptide in cancer-induced bone pain. Here, we evaluate the role of spinal NPY in the MRMT-1 rat model of cancer-induced bone pain. Our studies revealed an up-regulation of NPY-immunoreactivity in the dorsal horn of cancer-bearing rats 17 days after inoculation, which could be a compensatory antinociceptive response. Consistent with this interpretation, intrathecal administration of NPY to rats with cancer-induced bone pain caused a reduction in nociceptive behaviors that lasted up to 150 min. This effect was diminished by both Y1 (BIBO3304) and Y2 (BIIE0246) receptor antagonists, indicating that both receptors participate in mediating the antinociceptive effect of NPY. Y1 and Y2 receptor binding in the spinal cord was unchanged in the cancer state as compared to sham-operated rats, consistent with the notion that increased NPY results in a net antinociceptive effect in the MRMT-1 model. In conclusion, the data indicate that NPY is involved in the spinal nociceptive signaling of cancer-induced bone pain and could be a new therapeutic target for patients with this condition.

Injectable nanocomposite analgesic delivery system for musculoskeletal pain management.

Musculoskeletal pain is a major health issue which results from surgical procedures (i.e. total knee and/or hip replacements and rotator cuff repairs), as well as from non-surgical conditions (i.e. sympathetically-mediated pain syndrome and occipital neuralgia). Local anesthetics, opioids or corticosteroids are currently used for the pain management of musculoskeletal conditions. Even though local anesthetics are highly preferred, the need for multiple administration presents significant disadvantages. Development of unique delivery systems that can deliver local anesthetics at the injection site for prolonged time could significantly enhance the therapeutic efficacy and patient comfort. The goal of the present study is to evaluate the efficacy of an injectable local anesthetic nanocomposite carrier to provide sustained analgesic effect. The nanocomposite carrier was developed by encapsulating ropivacaine, a local anesthetic, in lipid nanocapsules (LNC-Rop), and incorporating the nanocapsules in enzymatically crosslinked glycol chitosan (0.3GC) hydrogels. Cryo Scanning Electron Microscopic (Cryo SEM) images showed the ability to distribute the LNCs within the hydrogel without adversely affecting their morphology. The study demonstrated the feasibility to achieve sustained release of lipophilic molecules from the nanocomposite carrier in vitro and in vivo. A rat chronic constriction injury (CCI) pain model was used to evaluate the efficacy of the nanocomposite carrier using thermal paw withdrawal latency (TWL). The nanocomposite carriers loaded with ropivacaine and dexamethasone showed significant improvement in pain response compared to the control groups for at least 7 days. The study demonstrated the clinical potential of these nanocomposite carriers for post-operative and neuropathic pain. STATEMENT OF SIGNIFICANCE: Acute or chronic pain associated with musculoskeletal conditions is considered a major health issue, with healthcare costs totaling several billion dollars. The opioid crisis presents a pressing clinical need to develop alternative and effective approaches to treat musculoskeletal pain. The goal of this study was to develop a long-acting injectable anesthetic formulation which can sustain a local anesthetic effect for a prolonged time. This in turn could increase the quality of life and rehabilitation outcome of patients, and decrease opioid consumption. The developed injectable nanocomposite demonstrated the feasibility to achieve prolonged pain relief in a rat chronic constriction injury (CCI) model.

Suppression of HDAC2 in Spinal Cord Alleviates Mechanical Hyperalgesia and Restores KCC2 Expression in a Rat Model of Bone Cancer Pain.

Epigenetic modulation participates in the mechanism of multiple types of pathological pain, so targeting the involved regulators may be a promising strategy for pain treatment. Our previous research identified the analgesic effect of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on mechanical hyperalgesia in a rat model of bone cancer pain (BCP) via restoration of µ-opioid receptor (MOR) expression. However, the specific types of HDACs contributing to BCP have not been explored. The present study investigated the expression pattern of some common HDACs and found that HDAC2 was up-regulated in a time-dependent manner in the lumbar spinal cord of BCP rats. TSA application suppressed HDAC2 expression in cultured PC12 cells and reversed the augmented HDAC2 in BCP rats. An RNA-interfering strategy confirmed the essential role of HDAC2 in the modulation of mechanical hyperalgesia following tumor cell inoculation, and we further examined its possible downstream targets. Notably, HDAC2 knock-down did not restore MOR expression, but it robustly reversed the down-regulation of potassium-chloride cotransporter 2 (KCC2). The impaired KCC2 expression is a vital mechanism of many types of pathological pain. Therefore, our results demonstrated that HDAC2 in spinal cord contributed to the mechanical hyperalgesia in BCP rats, and this effect may be associated with KCC2 modulation.

Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats.

Neonatal handling (NH) of male rat pups strongly attenuates stress response and stress-induced persistent muscle hyperalgesia in adults. Because female sex is a well established risk factor for stress-induced chronic muscle pain, we explored whether NH provides resilience to stress-induced hyperalgesia in adult female rats. Rat pups underwent NH, or standard (control) care. Muscle mechanical nociceptive threshold was assessed before and after water avoidance (WA) stress, when they were adults. In contrast to male rats, NH produced only a modest protection against WA stress-induced muscle hyperalgesia in female rats. Gonadectomy completely abolished NH-induced resilience in male rats but produced only a small increase in this protective effect in female rats. The administration of the antiestrogen drug fulvestrant, in addition to gonadectomy, did not enhance the protective effect of NH in female rats. Finally, knockdown of the androgen receptor by intrathecal antisense treatment attenuated the protective effect of NH in intact male rats. Together, these data indicate that androgens play a key role in NH-induced resilience to WA stress-induced muscle hyperalgesia. PERSPECTIVE: NH induces androgen-dependent resilience to stress-induced muscle pain. Therefore, androgens may contribute to sex differences observed in chronic musculoskeletal pain and its enhancement by stress.

Investigation of biomarkers alterations after an acute tissue trauma in human trapezius muscle, using microdialysis.

Alterations in muscle milieu are suggested as important activity of peripheral drive in patients with chronic musculoskeletal pain (CMP). Microdialysis (MD) has been used in monitoring altered metabolic response pattern in muscles. However, the insertion of MD probe causes a local tissue trauma. Whether and how metabolites in trapezius muscle are affected by acute tissue trauma is unknown. Hence, this study investigated the metabolic response and nociceptive reaction of the tissue following MD probe insertion in patients with CMP and healthy individuals. Fifty-nine patients and forty pain-free volunteers were recruited. Pressure pain thresholds (PPTs) were obtained at the trapezius and tibialis muscles. Pain questionnaires determined the levels of pain related aspects. MD (20 kDa cut-off) was performed in the trapezius and samples were collected within 40 min. Interstitial concentration of the metabolites was analyzed by a two-way-mixed-ANOVA. The metabolic response pattern changed over time and alterations in the level of metabolites could be seen in both CMP and healthy controls. Pain questionnaires and pain intensities manifested clinical aspects of pain closely to what CMP patients describe. Analyzing metabolites due to acute tissue trauma by aid of MD may be a useful model to investigate altered metabolic response effect in CMP.