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continue to illustrate the complexity mechanistic research in the field of manual therapy and nonpharmacological treatment of musculoskeletal-related pain. Two articles in Volume II address assessment of peripheral inflammatory biomarkers following nonpharmacological interventions, while the remaining articles address either accurately measuring mechanical forces delivered during manual therapy treatment, or the clinical effects of combined core stability exercises and manual therapy on sacroiliac joint dysfunction.The sole preclinical article (Dutra et al.) investigated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) combined with exercise (swimming) in mice with hindpaw inflammation induced by injection of Freund's complete adjuvant. Mice were treated with either 30 minutes of swimming alone, or in combination with 10, 20, or 30 minutes of pVNS (via the auricular nerve branch in the left ear) over 4 consecutive days. Study outcomes included behavioral tests (i.e. edema, paw temperature, mechanical hyperalgesia) and changes in inflammatory cytokines and interleukin-10 [IL-10]) in the spinal cord and hindpaw tissues. It was found 20 minutes of pVNS prolonged the mechanical antihyperalgesic effect for up to 2 hours, 30 33 minutes of pVNS prolonged this antihyperalgesic effect up to 7 hours, and no effect of pVNS was 34 demonstrated on either paw edema or paw temperature. While swimming by itself failed to alter IL-6 or 35 IL-10 levels in the paw or spinal cord tissue, combined swimming and pVNS reduced IL-6 levels in both 36 hindpaw and spinal cord tissues, and IL-10 in just the spinal cord. From this study, we see the benefit of 37 combining nonpharmacological interventions (exercise and pVNS) on mechanical antihyperalgesia and 38 the reduction of peripheral/central inflammatory cytokines. This study did not determine the precise 39 physiological mechanisms responsible for these changes, but it thought that pVNS modulates activation 40 of the HPA axis which influences the main organs of the immune system which synthesize pro-41 inflammatory cytokines, and/or that pVNS contributes to the production of pro-resolutive mediators 42 such as resolverins and maresins. These findings contribute to a growing number of studies investigating 43 the beneficial effects of combining of various types of exercise with pVNS to modulating pain-related 44 inflammatory cytokines and other pain biomarkers for more effective clinical pain management. 45In addition to the preclinical study investigating inflammatory cytokine modulation with the 46 nonpharmalogical interventions of exercise and pVNS, Gevers-Montoro et al. investigated whether 47 urinary levels of pro-inflammatory cytokine TNF-α could be beneficial in predicting clinical outcomes 48 and/or characteristics of individuals with chronic primary low back pain (CPLBP). Changes in urinary TNF-49 α concentrations were compared between twenty-four CPLBP patients who underwent spinal 50 manipulation treatment (8 visits) and asymptomatic age-matched controls. Concentrations of urinary 51 TNF-α were elevated at baseline for the CPLBP group compared to asymptomatic controls, with patients 52 with persistent CPLBP showing higher TNF-α levels than those experiencing episodic CPLBP. These 53 findings suggest that urinary TNF-α concentrations may potentially be useful as a potential patient subgroup sample size warrants caution with data interpretation. Pain intensity and the degree of 56 disability were significantly reduced with spinal manipulation, however changes in TNF-α did not predict 57 follow-up values intensity, nor disability. As an observational study with a small sample size and 58 lack of a control intervention group, study changes could not be attributed to the intervention or any 59 other factors. However, future placebo-controlled studies will help the specific relationship 60 between biomarker change, manual therapy delivery characteristics, and positive clinical outcomes. 61 Delivery characteristics of manual therapy was the topic of the third article (Siciliano et al.). 62Accurately measuring applied mechanical forces during nonpharmacological treatments such as spinal 63 manipulation, joint mobilization, and massage is crucial to determining the potential relationship 64 between manual therapy application/dosage and positive clinical outcomes. This article is a case report 65 of a patient diagnosed with discogenic sciatica with a sequestered disc fragment at L5 and a motor 66 deficit of the lower left extremity who underwent nonpharmacological treatment in the form of Cox 67 Technique Flexion Distraction Decompression spinal manipulation, electrical muscle stimulation, infra-68 red light therapy, and a home exercise program. Force cells embedded within the instrumented 69 treatment table accurately recorded bi-directional applied mechanical forces and motion data which 70 then can be used to ensure objective treatment consistency and reproducibility by the treating clinician. 71 Applied forces at specific flexion angles during treatment protocols were reported. The patient 72 responded well to this nonsurgical treatment. The ability to accurately and reliably measure applied 73 forces during manual therapy treatment may be used in future manual therapy studies to help 74 determine the optimal delivery characteristics and positive clinical outcomes. While there remains a great need for more preclinical and clinical nonpharmacologic 86 mechanistic-oriented studies, studies that better define clinical outcomes as well as determine optimal 87 nonpharmacological delivery characteristics will only serve to increase public acceptance and utilization 88 of these interventions in the management of musculoskeletal pain. 89

Background: Musculoskeletal pain disorders are among the leading causes of years lived with disability worldwide representing a significant burden to society. Studies investigating a “nociceptive-fusimotor” relationship using experimentally-induced pain/noxious stimuli and muscle spindle afferent (MSA) response have been published over several decades. The purpose of this scoping review was to systematically identify and summarize research findings related to the impact of experimentally-induced pain or noxious stimulation on direct MSA discharge/response. Methods: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane and Embase were searched from database inception to August 2020. Eligible studies were: (a) published in English; (b) clinical or pre-clinical studies; (c) original data studies; (d) included the investigation of MSA response to experimentally-induced pain or noxious stimulation; (e) included quantification of at least one direct physiological measure associated with MSA activity/response. Two-phase screening procedures were conducted by a pair of independent reviewers and data extracted from eligible studies. Results: The literature search resulted in 195 articles of which 23 met inclusion criteria. Six studies (26%) were classified as clinical and 17 (74%) as pre-clinical. Two clinical studies investigated the effects of sacral dermatome pin-pricking on MSA response, while the remaining 4 studies investigated the effects of tonic muscle and/or skin pain induced by injection/infusion of hypertonic saline into the tibialis anterior muscle or subdermal tissues. In pre-clinical studies, muscle pain was induced by injection of noxious substances or the surgical removal of the meniscus at the knee joint. Conclusion: Clinical studies in awake humans reported that experimentally-induced pain did not affect, or else slightly decreased MSA spontaneous discharge and/or response during weak dorsiflexor muscle contraction, thus failing to support an excitatory nociceptive-fusimotor relationship. However, a majority of pre-clinical studies indicated that ipsilateral and contralateral muscle injection of noxious substances altered MSA resting discharge and/or response to stretch predominately through static fusimotor reflex mechanisms. Methodological differences (use of anesthesia, stretch methodology, etc.) may ultimately be responsible for the discrepancies between clinical and pre-clinical findings. Additional investigative efforts are needed to reconcile these discrepancies and to clearly establish or refute the existence of nociceptive-fusimotor relationship in muscular pain.

Limitations of this preliminary study include a small sample size, non-standardized number and duration of treatments, and lack of a sham treatment group. [...]caution must be exercised in interpretating this early study measuring changes in urine pro-inflammatory cytokines associated with non-pharmacological treatment. While most of nociceptive-related research has focused on primary pain receptors and/or afferent cortical activity distribution, the impact of efferent motor processes on sensory processing has received growing interest of late as the motor system is becoming recognized to play important roles in pain management. William R. Reed1*, Kenneth A. Weber II2 and Daniel F. Martins3 * 1Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, United States * 2Division of Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, United States * 3Experimental Neuroscience Laboratory (LaNEx), Postgraduate Program in Health Sciences, University of Southern Santa Catarina - UNISUL, Palhoça, Brazil

This study aimed to evaluate the potential adverse effects of the dermal administration of Dillenia indica Linnaeus (D. indica) fruit extract in healthy rodents; the extract was standardized to betulinic acid. In the initial phase, the acute effects were evaluated on the skin application site of a single extract dose. A skin irritation test was performed in male Wistar rats (n = 8/group) receiving the extract (50-150 mg/mL) with betulinic acid (0.5-1.5%, respectively). A photosensitivity test was performed in male BALB/c mice (n = 6/group) receiving the extract (150 mg/mL). Afterwards, other BALB/c mice (n = 20, male:female, 1:1) were used to assess the systemic alterations caused by 14 daily repeated doses (150 mg/mL) by monitoring the effects on mortality, body morphology, behavior, nutrition status, neuromotor reactions, organ morphology and weight, and blood tests. At this time, 0.5 mg/mL clobetasol was used as the positive control. The skin irritation index suggested that negligible skin irritation had occurred, even when the extract was applied to the rat skin at 150 mg/mL. However, the extract acted as a photosensitizer on mouse skin, showing a photosensitizing activity close to that of 10 mg/mL 5-methoxypsoralen. Repeated doses caused no mouse mortality, aggressiveness, piloerection, diarrhea, convulsions, neuromotor alterations or nutrition status changes. The mouse organ weights did not change, and the mice did not have alterations in their blood compositions. Clobetasol caused a reduction in the mononuclear leukocyte numbers. In general, the data suggest that the extract was safe in healthy rodents but indicate that caution should be taken with the photosensitizing activity; in addition, this activity should be further explored as it may be useful for phototherapeutic drug development.

The present study was undertaken to explore the relative contributions of Cav3.2 T-type channels to mediating the antihyperalgesic activity of joint manipulation (JM) therapy. We used the chronic constriction injury model (CCI) to induce peripheral neuropathy and chronic pain in male mice, followed by JM. We demonstrate that JM produces long-lasting mechanical anti-hyperalgesia that is abolished in Cav3.2 null mice. Moreover, we found that JM displays a similar analgesic profile as the fatty acid amide hydrolase inhibitor URB597, suggesting a possible converging mechanism of action involving endocannabinoids. Overall, our findings advance our understanding of the mechanisms through which JM produces analgesia.

Complex regional pain syndrome type I (CRPS-I) is a condition that responds poorly to treatments. The role of omega-3 fatty acids in the treatment of inflammatory disorders is well described in the literature; however, few studies have evaluated its therapeutic benefits in different types of pain. We evaluated the potential antihyperalgesic and anti-inflammatory effects of preventive omega-3 supplementation in an animal model of CRPS-I. In experiment 1, Swiss female mice were supplemented for 30 days with omega-3 before the induction of the CRPS-I model and 14 days after. Mechanical hyperalgesia was evaluated at baseline and from the 4th to the 14th day after CPRS-I induction along with open field locomotor activity after 30 days of supplementation. In experiment 2, Swiss female mice were supplemented for 30 days with omega-3 and then subjected to the CRPS-I model. Twenty-four hours later the animals were euthanized, and tissue samples of the spinal cord and right posterior paw muscle were taken to measure pro-inflammatory cytokine TNF and IL-1β concentrations. Omega-3 supplementation produced antihyperalgesic and anti-inflammatory effects, as well as reducing pro-inflammatory cytokine concentrations, without altering the animals' locomotion. No open field locomotor changes were found. The 30-day supplementation at the tested dose was effective in the CRPS-I model.

Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Spinal mobilization (SM) is a non-pharmacological approach recommended by most clinical guidelines for LBP, but greater utilization and treatment optimization are hampered by a lack of mechanistic knowledge underlying its hypoalgesic clinical effects. Groups of female Sprague-Dawley rats received unilateral trunk (L5 vertebral level) injections (50 μl) of either vehicle (phosphate-buffer solution, PBS; VEH) or nerve growth factor (NGF; 0.8 μM) on Days 0 and 5 with or without daily L5 SM (VEH, NGF, VEH + SM, VEH + SM). Daily passive SM (10 min) was delivered by a feedback motor (1.2 Hz, 0.9N) from Days 1 to 12. Changes in pain assays were determined for mechanical and thermal reflexive behavior, exploratory behavior (open field events) and spontaneous pain behavior (rat grimace scale). On Day 12, lumbar (L1-L6) dorsal root ganglia (DRG) were harvested bilaterally and calcitonin gene-related peptide (CGRP) positive immunoreactive neurons were quantified from 3 animals (1 DRG tissue section per segmental level) per experimental group. NGF induced bilateral trunk (left = 0.006, right = 0.001) mechanical hyperalgesia and unilateral hindpaw allodynia ( = 0.006) compared to the vehicle group by Day 12. Additionally, we found for the first time that NGF animals demonstrated decreased exploratory behaviors (total distance traveled) and increased grimace scale scoring compared to the VEH group. Passive SM prevented this development of local (trunk) mechanical hyperalgesia and distant (hindpaw) allodynia, and normalized grimace scale scores. NGF increased CGRP positive immunoreactive neurons in ipsilateral lumbar DRGs compared to the VEH group ([L1] = 0.02; [L2] = 0.007) and SM effectively negated this increase in pain-related neuropeptide CGRP expression. SM prevents the development of local (trunk) NGF-induced mechanical hyperalgesia and distant (hindpaw) allodynia, in part, through attenuation of CGRP expression in lumbar DRG sensory neurons. NGF decreases rat exploratory behavior and increases spontaneous pain for which passive SM acts to mitigate these pain-related behavioral changes. These initial study findings suggest that beginning daily SM soon after injury onset might act to minimize or prevent the development of LBP by reducing production of pain-related neuropeptides.

Several studies in humans have reported that improved pain control is associated with exercise in a variety of painful conditions, including osteoarthritis, fibromyalgia, and neuropathic pain. Despite the growing amount of experimental data on physical exercise and nociception, the precise mechanisms through which high-intensity exercise reduces pain remain elusive. Since the glutamatergic system plays a major role in pain transmission, we firstly analyzed if physical exercise could be able to decrease glutamate-induced nociception through G-protein-coupled receptor (G-PCR) activation. The second purpose of this study was to examine the effect of exercising upon phosphorylation of protein kinase A (PKA) isoforms induced by intraplantar (i.pl.) glutamate injection in mice. Our results demonstrate that high-intensity swimming exercise decreases nociception induced by glutamate and that i.pl. or intrathecal injections of cannabinoid, opioid, and adenosine receptor antagonists, AM281, naloxone, and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), respectively, prevent this effect. Furthermore, the peripheral A 1 and opioid receptors, but not CB 1 , are also involved in exercise’s effect. We also verified that glutamate injection increases levels of phosphorylated PKA (p-PKA). High-intensity swimming exercise significantly prevented p-PKA increase. The current data show the direct involvement of the glutamatergic system on the hyponociceptive effect of high-intensity swimming exercise as well as demonstrate that physical exercise can activate multiple intracellular pathways through G-PCR activation, which share the same endogenous mechanism, i.e., inhibition of p-PKA.

Physical therapists frequently use joint mobilization therapy techniques to treat people with musculoskeletal dysfunction and pain. Several studies suggest that endogenous adenosine may act in an analgesic fashion in various pain states. The purpose of this study was to investigate the contribution of the adenosinergic system on the antihyperalgesic effect of ankle joint mobilization (AJM). This was a experimental study. To test the hypothesis that the adrenosinergic system is involved in the antihyperalgesic effect of AJM, mice (25-35 g) submitted to plantar incision surgery were used as a model of acute postoperative pain. The mice were subjected to AJM for 9 minutes. Withdrawal frequency to mechanical stimuli was assessed 24 hours after plantar incision surgery and 30 minutes after AJM, adenosine, clonidine, or morphine treatments. The adenosinergic system was assessed by systemic (intraperitoneal), central (intrathecal), and peripheral (intraplantar) administration of caffeine. The participation of the A1 receptor was investigated using a selective adenosine A1 receptor subtype antagonist. In addition, previous data on the involvement of the serotonergic and noradrenergic systems in the antihyperalgesic effect of AJM were confirmed. Ankle joint mobilization decreased mechanical hyperalgesia, and this effect was reversed by pretreatment of the animals with caffeine given by intraperitoneal, intraplantar, and intrathecal routes. In addition, intraplanar and intrathecal administrations of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, a selective adenosine A1 subtype receptor antagonist) or systemic administration of yohimbine or ρ-chlorophenylalanine methyl ester hydrochloride (PCPA) blocked the antihyperalgesia induced by AJM. The results are limited to animal models and cannot be generalized to acute pain in humans. This study demonstrated the involvement of the adenosinergic system in the antihyperalgesic effect of AJM in a rodent model of pain and provides a possible mechanism basis for AJM-induced relief of acute pain.

Background The intervertebral disc is a known back pain generator and is frequently the focus of spinal manipulative therapy evaluation and treatment. The majority of our current knowledge regarding intradiscal pressure (IDP) changes related to spinal manual therapy involves cadaveric studies with their inherent limitations. Additional in vivo animal models are needed to investigate intervertebral disc physiological and molecular mechanisms related to spinal manipulation and spinal mobilization treatment for low back disorders. Methods Miniature pressure catheters (Millar SPR-1000) were inserted into either the L4-L5 or L5-L6 intervertebral disc of 3 deeply anesthetized adult cats (Oct 2012-May 2013). Changes in IDP were recorded during delivery of instrument-assisted spinal manipulation (Activator V® and Pulstar®) and motorized spinal flexion with/without manual spinous process contact. Results Motorized flexion of 30° without spinous contact decreased IDP of the L4-L5 disc by ~ 2.9 kPa, while physical contact of the L4 spinous process decreased IDP an additional ~ 1.4 kPa. Motorized flexion of 25° with L5 physical contact in a separate animal decreased IDP of the L5-L6 disc by ~ 1.0 kPa. Pulstar® impulses (setting 1–3) increased IDP of L4-L5 and L5-L6 intervertebral discs by ~ 2.5 to 3.0 kPa. Activator V® (setting 1–4) impulses increased L4-L5 IDP to a similar degree. Net changes in IDP amplitudes remained fairly consistent across settings on both devices regardless of device setting suggesting that viscoelastic properties of in vivo spinal tissues greatly dampen superficially applied manipulative forces prior to reaching deep back structures such as the intervertebral disc. Conclusions This study marks the first time that feline in vivo changes in IDP have been reported using clinically available instrument-assisted spinal manipulation devices and/or spinal mobilization procedures. The results of this pilot study indicate that a feline model can be used to investigate IDP changes related to spinal manual therapy mechanisms as well as the diminution of these spinal manipulative forces due to viscoelastic properties of the surrounding spinal tissues. Additional investigation of IDP changes is warranted in this and/or other in vivo animal models to provide better insights into the physiological effects and mechanisms of spinal manual therapy at the intervertebral disc level.