Quantitative Sensory Testing Protocols to Evaluate Central and Peripheral Sensitization in Knee OA: A Scoping Review.

OBJECTIVE: This scoping review analyzed various quantitative sensory testing methodologies used in the assessment of sensitization and how sensitization is defined in people with knee osteoarthritis. DESIGN: A scoping review. SETTING: All clinical and research settings. SUBJECTS: Non-surgical adults with knee osteoarthritis. METHODS: This scoping review was guided by existing scoping review methodologies. Relevant studies were extracted from the following electronic databases: Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Allied and Complementary Medicine Database, and the Cumulative Index to Nursing Allied Health Literature. Abstract and full article screening and data extraction were performed in pairs. Information on quantitative sensory testing techniques and parameters was extracted and summarized in tables. General and technique specific definitions of sensitization were extracted from included texts. RESULTS: Our search yielded 4,199 articles, of which 50 were included in our review. The most common quantitative sensory test was pressure pain threshold. In total 28 unique testing sites were found speaking to the high degree of variability between studies. Sensitization was poorly defined with only 8 studies fully operationalizing it, 22 partially, and the remainder did not provide sufficient information to meet our criteria. CONCLUSIONS: This scoping review has provided an overview of the most common methods of quantitative sensory testing being implemented in the assessment of nervous system sensitization to nociceptive signaling in people with knee osteoarthritis. This study provides a foundation for future development of quantitative sensory testing methodology for research and clinical practice in the osteoarthritis population.

Correlation Between Central Sensitization and Remote Muscle Performance in Individuals With Chronic Low Back Pain.

OBJECTIVE: The purpose of this study was to examine associations between the degree of central sensitization (CS) and remote muscle performance in people with chronic low back pain (CLBP). METHODS: The 2011 fibromyalgia (FM) criteria and severity scales (2011 FM survey) were used as a surrogate measure of CS to divide the participants into 2 groups: FM-positive CLBP and FM-negative CLBP. Measures related to central sensitization included the 2011 FM survey and pressure pain threshold of the thumbnail. Measures related to muscle performance included neck flexor muscle strength and endurance and plantar flexor muscle strength. Between-groups and correlation analyses were performed. RESULTS: Sixty people with CLBP were enrolled (30 FM-positive, 30 FM-negative). There was no significant difference between the subgroups in age, sex, or pain duration (P > .05). The FM-positive CLBP group showed poorer neck flexor muscle endurance (P = .01) and plantar flexor muscle strength (P = .002) than the FM-negative CLBP group, whereas neck flexor muscle strength was not different between the groups (P = .175). Scores for FM and values for pressure pain thresholds of the thumbnail were associated with neck flexor muscle strength (respectively, r = -0.320, P = .013, and r = 0.467, P < .001), endurance (r = -0.242, P < .001, and r = 0.335, P = .009), and plantar flexor muscle strength (r = -0.469, P < .001, and r = 0.500, P < .001). CONCLUSION: We found associations between the degree of CS and remote muscle strength and endurance, suggesting that poor remote muscle performance is possibly a clinical sign of CS in people with CLBP.

Can the Positional Release Technique Affect Central Sensitization in Patients With Chronic Tension-Type Headache? A Randomized Clinical Trial.

OBJECTIVES: To investigate whether the positional release technique (PRT) affects central sensitization in patients with chronic tension-type headache (TTH). DESIGN: Randomized controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. SETTING: Two university neurology clinics. PARTICIPANTS: Patients (N=32) with TTH and myofascial trigger points (MTrP) in their cervical muscles. INTERVENTIONS: Patients in the PRT group received 10 treatment sessions for each of their MTrPs over the course of 5 weeks. All participants could use ibuprofen 200 mg for their headaches during the study. MAIN OUTCOME MEASURES: The primary outcome measure was brain metabolite profile. The secondary outcome measures were headache frequency and intensity, McGill score, and pressure pain threshold (PPT), which were evaluated in each participant during 5 weeks with proton magnetic resonance spectroscopy, patients' self-reports, the McGill Pain Questionnaire, and a pressure algometer. RESULTS: Analysis of the data from 26 patients showed that headache frequency (P=.001), headache intensity (P=.002), McGill score (P=.003), and local PPT (P=.003) changed significantly after PRT. The myo-inositol/creatine concentration ratio in the somatosensory cortex (P=.041) decreased significantly in the control group. Furthermore, there were significant differences between groups in headache frequency (P<.001), headache intensity (P<.001), McGill score (P<.001), local PPT (P=.004), distal PPT (P=.041), and glutamate-glutamine/creatine concentration ratio in the thalamus (P=.014). CONCLUSIONS: These findings indicate that PRT did not affect central sensitization in patients with TTH despite the improvement in clinical symptoms.

Nutritional intervention in chronic pain: an innovative way of targeting central nervous system sensitization?

INTRODUCTION: Few treatment programs for chronic pain nowadays take a dietary pattern or adipose status into account. AREAS COVERED: An important role of neuroinflammation in chronic pain is now well established, at least in part due to increased central nervous system glial activation. Based on preclinical studies, it is postulated that the interaction between nutrition and central sensitization is mediated via bidirectional gut-brain interactions. This model of diet-induced neuroinflammation and consequent central sensitization generates a rationale for developing innovative treatments for patients with chronic pain. Methods: An umbrella approach to cover the authors' expert opinion within an evidence-based viewpoint. EXPERT OPINION: A low-saturated fat and low-added sugar dietary pattern potentially decreases oxidative stress, preventing Toll-like receptor activation and subsequent glial activation. A low-saturated fat and low-added sugar diet might also prevent afferent vagal nerve fibers sensing the pro-inflammatory mediators that come along with a high-(saturated) fat or energy-dense dietary pattern, thereby preventing them to signal peripheral inflammatory status to the brain. In addition, the gut microbiota produces polyamines, which hold the capacity to excite N-methyl-D-aspartate receptors, an essential component of the central nervous system sensitization. Hence, a diet reducing polyamine production by the gut microbiota requires exploration as a therapeutic target for cancer-related and non-cancer chronic pain.

Distinct Patterns of Neural Habituation and Generalization in Children and Adolescents With Autism With Low and High Sensory Overresponsivity.

OBJECTIVE: Sensory overresponsivity (SOR), an atypical negative reaction to sensory stimuli, is highly prevalent in autism spectrum disorder (ASD). Previous work has related SOR to increased brain response in sensory-limbic regions. This study investigated where these atypical responses fall in three fundamental stages of sensory processing: arousal (i.e., initial response), habituation (i.e., change in response over time), and generalization of response to novel stimuli. Different areas of atypical response would require distinct intervention approaches. METHODS: Functional MRI was used to examine these patterns of neural habituation to two sets of similar mildly aversive auditory and tactile stimuli in 42 high-functioning children and adolescents with ASD (21 with high levels of SOR and 21 with low levels of SOR) and 27 age-matched typically developing youths (ages 8-17). The relationship between SOR and change in amygdala-prefrontal functional connectivity across the sensory stimulation was also examined. RESULTS: Across repeated sensory stimulation, high-SOR participants with ASD showed reduced ability to maintain habituation in the amygdala and relevant sensory cortices and to maintain inhibition of irrelevant sensory cortices. These results indicate that sensory habituation is a dynamic, time-varying process dependent on sustained regulation across time, which is a particular deficit in high-SOR participants with ASD. However, low-SOR participants with ASD also showed distinct, nontypical neural response patterns, including reduced responsiveness to novel but similar stimuli and increases in prefrontal-amygdala regulation across the sensory exposure. CONCLUSIONS: The results suggest that all children with autism have atypical brain responses to sensory stimuli, but whether they express atypical behavioral responses depends on top-down regulatory mechanisms. Results are discussed in terms of targeted intervention approaches.

Low-intensity muscle contraction exercise following the onset of arthritis improves hyperalgesia via reduction of joint inflammation and central sensitization in the spinal cord in a rat model.

We examined the effect of immobilization, low-intensity muscle contraction exercise, and transcutaneous electrical nerve stimulation (TENS) on tissue inflammation and acute pain following the onset of arthritis in a rat model. Sixty Wistar rats were divided into five groups: (1) Arthritis group, (2) arthritis and immobilization (Immobilization group), (3) arthritis and low intensity muscle contraction (Exercise group), (4) arthritis and TENS (TENS group), and (5) sham arthritis (Sham group). Arthritis was induced in the right knee joints by single injection of 3% kaolin and carrageenan. Immobilization of the right hindlimb was conducted by full extension of the right knee joints and full plantar flexion of the ankle joints using a plaster cast for 7 days after injection. The right quadriceps muscles were subjected to electrical stimulation (frequency: 50 Hz; intensity: 2-3 mA) for 20 min/day as contraction exercise for one week. TENS was delivered at 20 min/day for one week (frequency: 50 Hz; intensity: 1 mA). The pressure pain threshold (PPT) and paw withdrawal response (PWR) were evaluated at 1 and 7 days after injection. We also analyzed the number of CD68-positive cells in the synovium by immunohistochemistry and determined the expression level of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn with immunofluorescence. Improvements of both PPT and PWR were observed in the Exercise group at 7 days after injection compared to those of the Arthritis and Immobilization groups, although only improvement of PPT was observed in the TENS group. The number of CD68-positive cells in the synovium and CGRP expression in the dorsal horn decreased only in the Exercise group. These results suggested that low-intensity muscle contraction exercise might be a better treatment for reduction of arthritis-induced inflammation and acute pain compared to immobilization and TENS.

Current understanding of thalamic structure and function in migraine.

OBJECTIVE: To review and discuss the literature on the role of thalamic structure and function in migraine. DISCUSSION: The thalamus holds an important position in our understanding of allodynia, central sensitization and photophobia in migraine. Structural and functional findings suggest abnormal functional connectivity between the thalamus and various cortical regions pointing towards an altered pain processing in migraine. Pharmacological nociceptive modulation suggests that the thalamus is a potential drug target. CONCLUSION: A critical role for the thalamus in migraine-related allodynia and photophobia is well established. Additionally, the thalamus is most likely involved in the dysfunctional pain modulation and processing in migraine, but further research is needed to clarify the exact clinical implications of these findings.

Trait anxiety and sensory processing profile characteristics in patients with non-specific chronic low back pain and central sensitisation - A pilot observational study.

INTRODUCTION: People with non-specific chronic low back pain (NSCLBP) and central sensitisation (CS) exhibit sensory processing alterations, somatosensory hypersensitivity and differences in the brain's emotional networks. The concept that CS relates to pre-morbid trait sensory processing and anxiety characteristics is unknown. The aims of this pilot observational study were to test concept plausibility in a NSCLBP population with central sensitisation by investigating: 1) the range of Central Sensitisation Inventory scores, to determine the extent of symptoms of central sensitisation, 2) whether there are identifiable patient characteristics of trait anxiety and trait sensory profile differences; and 3) whether potential relationships exist between trait anxiety, trait sensory profiles and the extent of symptoms of central sensitisation. METHODS: People with NSCLBP and CS were recruited from physiotherapy outpatient clinics in New Zealand and the United Kingdom. Outcomes included the Central Sensitisation Inventory (CSI), Adolescent/Adult Sensory Profile and the State/Trait Anxiety Inventory (trait section) with the Marlowe Crowne Sociable Desirability Scale. Descriptive and non-parametric tests for correlation were used to analyse the data, p=<0.05. RESULTS: Of the 21 people recruited, 16 (76.2%) had CSI scores ≥40 in association with 1) an abnormally high prevalence of extreme scores of a) high trait Sensory Sensitive, Sensation Avoiding and Low Registration sensory profiles and b) low trait Sensation Seeking profile, 2) high trait anxiety sub-types and 3) minimal low trait anxiety. Moderate correlations were identified between trait sensory profiles and 1) CS pain (Sensory Sensitive R = 0.57, p < 0.01, CI = 0.07 to 0.88, p < 0.01, Sensation Seeking R = -0.47, p < 0.05, CI = -0.72 to -0.02) and 2) trait anxiety (Sensory sensitive: R = 0.65, p < 0.01, CI = 0.27 to 0.91) and Low Registration (R = 0.49, p < 0.05, CI = 0.03 to 0.84). The CSI scores moderately correlated with trait anxiety (R = 0.63, p < 0.01, CI = 0.22 to 0.86). CONCLUSION: These results provide concept plausibility that the extent of CS pain in people with NSCLBP might be associated with pre-morbid trait anxiety sub-types and abnormal trait sensory processing profiles. A larger study to confirm the findings is warranted.

Association Between Symptoms of Central Sensitization and Cognitive Behavioral Factors in People With Chronic Nonspecific Low Back Pain: A Cross-sectional Study.

OBJECTIVE: The objective of this cross-sectional study was to analyze the relationship between symptoms of central sensitization (CS) and important cognitive behavioral and psychosocial factors in a sample of patients with chronic nonspecific low back pain. METHODS: Participants with chronic nonspecific low back pain for at least 3 months were included in the study. They completed several questionnaires and a functional test. Pearson's correlation was used to analyze associations between symptoms of CS and pain behavior, functioning, pain, pain catastrophizing, kinesiophobia, and illness perceptions. Additionally, a between-group analysis was performed to compare patients with and without clinically relevant symptoms of CS. RESULTS: Data from 38 participants were analyzed. Significant associations were found between symptoms of CS and all other outcomes, especially current pain (r = 0.510, P = .001), mean pain during the past 7 days (r = 0.505, P = .001), and pain catastrophizing (r = 0.518, P = .001). Patients with clinically relevant symptoms of CS scored significantly worse on all outcomes compared with persons without relevant symptoms of CS, except on functioning (P = .128). CONCLUSIONS: Symptoms of CS were significantly associated with psychosocial and cognitive behavioral factors. Patients exhibiting a clinically relevant degree of symptoms of CS scored significantly worse on most outcomes, compared with the subgroup of the sample with fewer symptoms of CS.

Central Sensitization Is Modulated Following Trigger Point Anesthetization in Patients with Chronic Pain from Whiplash Trauma. A Double-Blind, Placebo-Controlled, Crossover Study.

Objective: Central sensitization (CS) with low peripheral pain thresholds (PPTs) is a common finding among patients with chronic pain after whiplash (CPWI). While it has been proposed that myofascial myofascial trigger points (MTrPs) may act as modulators of central sensitization, previously reported findings are conflicting and inconclusive. The present study was designed to investigate immediate responsiveness of CS to alterations in nociceptive input. Design: Controlled, double-blind, cross-over. Subjects: Thirty-one patients with chronic pain (trapezius myalgia) and CS after whiplash. Methods: Participants were referred by randomization to group A for injection of a single peripheral pain generator (MTrP or other discrete tender point) with local anesthetic or to group B for sham injection and cross-over. Documentation of PPT (Algometer), maximum jaw opening (caliper), and grip strength (Vigorimeter), as well as subjective overall pain (visual analog scale [VAS]), was made before and after each intervention. Results: Statistical analysis of data (Student's t test, analysis of variance) confirmed that peripheral pain thresholds were significantly higher and maximum jaw opening significantly greater after anesthetizing a focal pain generator in the trapezius, but not after a sham injection. In contrast with the objective variables, subjective generalized pain improved (VAS) after not only an injection of local anesthetic, but also, and to a similar extent, after a sham injection. Conclusions: CS, as expressed by lowered PPT, is a rapidly adjusting physiological response to nociceptive stimuli in some patients with chronic pain after whiplash. PPT are likely modulated by myofascial tender points in selected patients with CS. With reference to the present findings, surgical ablation of MTrPs is discussed as a potential treatment modality for CS.

Chronic Inflammatory Pain Impairs mGluR5-Mediated Depolarization-Induced Suppression of Excitation in the Anterior Cingulate Cortex.

The anterior cingulate cortex (ACC) is a critical hub for nociceptive perception and pain-related anxiety. Long-term synaptic plasticity in ACC was found to be important for chronic inflammatory pain and pain-related anxiety. As short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE) is involved in several conditions, such as chronic stress, epilepsy, and autism. However, it is still unknown whether DSE in the ACC is involved in the central sensitization of pain and anxiety. Using a whole-cell patch clamp, calcium imaging, western blot, and behavioral testing, we found that DSE was induced by a 2 s depolarization in postsynaptic pyramidal cells in ACC. DSE was mediated by endocannabinoid signaling and modulated by metabotropic glutamate receptor 5 (mGluR5). DSE was impaired by decreasing expression and dysfunction of mGluR5 in a mouse model of inflammatory pain induced by complete Freund's adjuvant. CDPPB, an mGluR5-positive allosteric modulator, could rescue hypersensitivity and anxiety-like behavior in this pain model. Our results demonstrated that mGluR5-mediated short-term plasticity in ACC may be a critical mechanism for chronic pain, and mGluR5 may potentially serve as a target of pain therapy, including treatments for hyperalgesia and anxiety.

Differential Desensitization Observed at Multiple Effectors of Somatic µ-Opioid Receptors Underlies Sustained Agonist-Mediated Inhibition of Proopiomelanocortin Neuron Activity.

Activation of somatic µ-opioid receptors (MORs) in hypothalamic proopiomelanocortin (POMC) neurons leads to the activation of G-protein-coupled inward rectifier potassium (GIRK) channels and hyperpolarization, but in response to continued signaling MORs undergo acute desensitization resulting in robust reduction in the peak GIRK current after minutes of agonist exposure. We hypothesized that the attenuation of the GIRK current would lead to a recovery of neuronal excitability whereby desensitization of the receptor would lead to a new steady state of POMC neuron activity reflecting the sustained GIRK current observed after the initial decline from peak with continued agonist exposure. However, electrophysiologic recordings and GCaMP6f Ca2+ imaging in POMC neurons in mouse brain slices indicate that maximal inhibition of cellular activity by these measures can be maintained after the GIRK current declines. Blockade of the GIRK current by Ba2+ or Tertiapin-Q did not disrupt the sustained inhibition of Ca2+ transients in the continued presence of agonist, indicating the activation of an effector other than GIRK channels. Use of an irreversible MOR antagonist and Furchgott analysis revealed a low receptor reserve for the activation of GIRK channels but a >90% receptor reserve for the inhibition of Ca2+ events. Altogether, the data show that somatodendritic MORs in POMC neurons inhibit neuronal activity through at least two effectors with distinct levels of receptor reserve and that differentially reflect receptor desensitization. Thus, in POMC cells, the decline in the GIRK current during prolonged MOR agonist exposure does not reflect an increase in cellular activity as expected.SIGNIFICANCE STATEMENT Desensitization of the µ-opioid receptor (MOR) is thought to underlie the development of cellular tolerance to opiate therapy. The present studies focused on MOR desensitization in hypothalamic proopiomelanocortin (POMC) neurons as these neurons produce the endogenous opioid ß-endorphin and are heavily regulated by opioids. Prolonged activation of somatic MORs in POMC neurons robustly inhibited action potential firing and Ca2+ activity despite desensitization of the MOR and reduced activation of a potassium current over the same time course. The data show that somatic MORs in POMC neurons couple to multiple effectors that have differential sensitivity to desensitization of the receptor. Thus, in these cells, the cellular consequence of MOR desensitization cannot be defined by the activity of a single effector system.

Detection of peripheral and central sensitisation at acupoints in patients with unilateral shoulder pain in Beijing: a cross-sectional matched case-control study.

OBJECTIVE: To investigate the pattern of experimental pain responses at acupoints in patients with unilateral shoulder pain. DESIGN: A cross-sectional matched study. SETTING: Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University. PARTICIPANTS: Volunteer samples of 60 participants (30 patients with unilateral shoulder pain, 30 healthy controls). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Pressure pain thresholds (PPTs) were measured at four acupoints-namely, Tianzong (SI 11), Jianliao (SJ 14), Jianyu (LI 15) and Jianzhen (SI 9), on the painful/non-painful side in patients with unilateral shoulder pain or healthy controls, respectively. The correlations between the Peripheral Sensitisation Index (PSI) and Central Sensitisation Index (CSI) were compared. RESULTS: Analysis showed significantly lower PPT values at acupoints on the painful side compared with the non-painful side in patients with shoulder pain (p<0.025). Meanwhile, PPTs on the non-painful side of these patients were lower than those on the ipsilateral side of healthy controls (p<0.025). No significant differences in PPT values were found between the non-acupoint of the painful/non-painful side in patients with shoulder pain and the ipsilateral side of healthy controls (p>0.05). Additionally, it was observed that the pressure pain assessment acupoints have a strong association with PSI and CSI; three acupoints, in particular, SJ 14, LI 15 and SI 9, showed a correlation with PSI and CSI. CONCLUSION: The results suggest the presence of peripheral and central sensitisation at acupoints in participants with unilateral shoulder pain. There exists an obvious relationship among the three acupoints SJ 14, LI 15 and SI 9, which are usually chosen to treat shoulder pain. The results provide evidence for the selection of acupoints to treat shoulder pain by acupuncture.

Advances in the Treatment of Neuropathic Pain.

Neuropathic pain is pain that arises as a direct consequence of a lesion or diseases affecting the somatosensory system. Treatments for neuropathic pain include pharmacological, nonpharmacological, and interventional therapies. Currently recommended first-line pharmacological treatments include antidepressants and anticonvulsants (gabapentin and pregabalin). However, in some cases, pharmacological therapy alone fails to give adequate control of the chronic pain. New techniques have been invented and have been proved effective on neuropathic pain, such as behavioral, cognitive, integrative, and physical therapies. In this review, we focused on the advances in the treatment of central neuropathic pain, diabetic peripheral neuropathy, postherpetic neuralgia, and cancer pain.

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes.

UNLABELLED: Thiazolidinedione drugs (TZDs) such as pioglitazone are approved by the U.S. Food and Drug Administration for the treatment of insulin resistance in type 2 diabetes. However, whether TZDs reduce painful diabetic neuropathy (PDN) remains unknown. Therefore, we tested the hypothesis that chronic administration of pioglitazone would reduce PDN in Zucker Diabetic Fatty (ZDF(fa/fa) [ZDF]) rats. Compared with Zucker Lean (ZL(fa/+)) controls, ZDF rats developed: (1) increased blood glucose, hemoglobin A1c, methylglyoxal, and insulin levels; (2) mechanical and thermal hyperalgesia in the hind paw; (3) increased avoidance of noxious mechanical probes in a mechanical conflict avoidance behavioral assay, to our knowledge, the first report of a measure of affective-motivational pain-like behavior in ZDF rats; and (4) exaggerated lumbar dorsal horn immunohistochemical expression of pressure-evoked phosphorylated extracellular signal-regulated kinase. Seven weeks of pioglitazone (30 mg/kg/d in food) reduced blood glucose, hemoglobin A1c, hyperalgesia, and phosphorylated extracellular signal-regulated kinase expression in ZDF. To our knowledge, this is the first report to reveal hyperalgesia and spinal sensitization in the same ZDF animals, both evoked by a noxious mechanical stimulus that reflects pressure pain frequently associated with clinical PDN. Because pioglitazone provides the combined benefit of reducing hyperglycemia, hyperalgesia, and central sensitization, we suggest that TZDs represent an attractive pharmacotherapy in patients with type 2 diabetes-associated pain. PERSPECTIVE: To our knowledge, this is the first preclinical report to show that: (1) ZDF rats exhibit hyperalgesia and affective-motivational pain concurrent with central sensitization; and (2) pioglitazone reduces hyperalgesia and spinal sensitization to noxious mechanical stimulation within the same subjects. Further studies are needed to determine the anti-PDN effect of TZDs in humans.

Hyperbaric oxygen therapy attenuates central sensitization induced by a thermal injury in humans.

BACKGROUND: Hyperbaric oxygen (HBO2 ) treatment has in animal experiments demonstrated antinociceptive effects. It was hypothesized that these effects would attenuate secondary hyperalgesia areas (SHAs), an expression of central sensitization, after a first-degree thermal injury in humans. METHODS: Seventeen healthy volunteers were examined during two sessions using a randomized crossover design. Volunteers were studied during control conditions (ambient pressure, FI O2 = 0.21) and during HBO2 (2.4 standard atmosphere, FI O2 = 1.0, 90 min) conditions in a pressure chamber. Quantitative sensory testing, including assessment of SHAs was performed. RESULTS: A statistically significant overall attenuation of SHAs was seen during the HBO2 sessions compared with the control-sessions (P = 0.011). In the eight volunteers starting with the HBO2 session, no difference in SHAs compared with control was demonstrated. However, in the nine volunteers starting with the control session, a statistical significant attenuation of SHAs was demonstrated in the HBO2 session (P = 0.004). CONCLUSIONS: The results indicate that HBO2 therapy in humans attenuates central sensitization induced by a thermal skin injury, compared with control. These new and original findings in humans corroborate animal experimental data. The thermal injury model may give impetus to future human neurophysiological studies exploring the central effects of hyperbaric oxygen treatment.

Reduction of Pain Sensitivity is Associated with the Response to Treatment in Women with Chronic Pelvic Pain.

OBJECTIVE: The objective of this study was to evaluate whether pain thresholds to electrical stimulation of the skin change in the response to treatment in women with chronic pelvic pain (CPP). METHODS: Fifty-eight women with persistent pelvic pain for at least 6 months, from a tertiary care setting, were included in this study. All women were evaluated before the therapeutic intervention and at 6 months of multidisciplinary treatment. To estimate the pain threshold, we used transcutaneous electrical nerve stimulation on the anterior surface of the nondominant arm. The intensity of clinical pain was estimated by a visual analog scale and by the McGill questionnaire. RESULTS: The mean of pain threshold increased from 14.2 to 17.4 after 6 months of treatment (P < 0.0001). The effect sizes of the increase of electrical pain threshold were 0.86 (95% CI, 0.38 to 1.34) in the group with pain reduction and 0.53 (95% CI, -0.08 to 1.15) in the group without pain reduction. CONCLUSION: The sensitivity to experimental pain was reduced after 6 months of multidisciplinary treatment for CPP. Our data provided additional evidence of central sensitization in women with CPP.

Anticipatory sensitization to repeated stressors: the role of initial cortisol reactivity and meditation/emotion skills training.

Anticipation may play a role in shaping biological reactions to repeated stressors-a common feature of modern life. We aimed to demonstrate that: (a) individuals who display a larger cortisol response to an initial stressor exhibit progressive anticipatory sensitization, showing progressively higher cortisol levels before subsequent exposures, and (b) attention/emotional skills training can reduce the magnitude of this effect on progressive anticipatory sensitization. Female school teachers (N=76) were randomly assigned to attention/emotion skills and meditation training or to a control group. Participants completed 3 separate Trier Social Stress Tests (TSST): at baseline (Session 1), post-training (Session 2), and five months post (Session 3). Each TSST session included preparing and delivering a speech and performing an arithmetic task in front of critical evaluators. In each session participants' salivary cortisol levels were determined before and after the stressor. Control participants with larger cortisol reactivity to the first stressor showed increasing anticipatory (pre-stressor) cortisol levels with each successive stressor exposure (TSST session)-suggesting progressive anticipatory sensitization. Yet this association was absent in the training group. Supplementary analyses indicated that these findings occurred in the absence of group differences in cortisol reactivity. Findings suggest that the stress response can undergo progressive anticipatory sensitization, which may be modulated by attention/emotion-related processes. An important implication of the construct of progressive anticipatory sensitization is a possible self-perpetuating effect of stress reactions, providing a candidate mechanism for the translation of short-to-long-term stress reactions.

Levo-tetrahydropalmatine attenuates the development and expression of methamphetamine-induced locomotor sensitization and the accompanying activation of ERK in the nucleus accumbens and caudate putamen in mice.

Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from corydalis and has been used in many traditional Chinese herbal preparations for its analgesic, sedative, and hypnotic properties. Previous studies indicated that l-THP has modest antagonist activity against dopamine receptors and thus it might have potential therapeutic effects on drug addiction. However, whether and how l-THP contributes to methamphetamine (METH)-induced locomotor sensitization remains unclear. Therefore, the current study aims to examine the roles of l-THP in the development and expression of METH-induced locomotor sensitization as well as the accompanying extracellular-regulated kinase (ERK) activation in the nucleus accumbens (NAc), caudate putamen (CPu) and prefrontal cortex (PFc) in mice. We found that moderate doses of METH (0.5 and 2 mg/kg) induced hyper-locomotor activity in mice on all METH injection days whereas high dose of METH (5 mg/kg)-treated mice displayed only acute locomotor response to METH and severe stereotyped behaviors on the first day after drug injection. Interestingly, only 2 mg/kg dose of METH-induced locomotor sensitization which was accompanied by the activation of ERK1/2 in the NAc and CPu in mice. Although l-THP (5 and 10 mg/kg) per se did not induce obvious changes in locomotor activities in mice, its co-administration with METH could significantly attenuate acute METH-induced hyper-locomotor activity, the development and expression of METH-induced locomotor sensitization, and the accompanying ERK1/2 activation in the NAc and CPu. These results suggest that l-THP has potential therapeutic effect on METH-induced locomotor sensitization, and the underlying molecular mechanism might be related to its inhibitory effect on ERK1/2 phosphorylation in the NAc and CPu.