Shou-Wei Yue

Myofascial trigger points: spontaneous electrical activity and its consequences for pain induction and propagation.

Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activity at myofascial trigger point originates from the extrafusal motor endplate. The spontaneous electrical activity represents focal muscle fiber contraction and/or muscle cramp potentials depending on trigger point sensitivity. Local pain and tenderness at myofascial trigger points are largely due to nociceptor sensitization with a lesser contribution from non-nociceptor sensitization. Nociceptor and non-nociceptor sensitization at myofascial trigger points may be part of the process of muscle ischemia associated with sustained focal muscle contraction and/or muscle cramps. Referred pain is dependent on the sensitivity of myofascial trigger points. Active myofascial trigger points may play an important role in the transition from localized pain to generalized pain conditions via the enhanced central sensitization, decreased descending inhibition and dysfunctional motor control strategy.

Nociceptive and non-nociceptive hypersensitivity at latent myofascial trigger points.

ObjectiveThe aim of the study was to evaluate whether or not there exists nociceptive and non-nociceptive hypersensitivity at latent myofascial trigger points (MTrPs). MethodsEleven healthy volunteers participated in this study, which consisted of 3 sessions of electromyography-guided intramuscular injection with a minimum of a week interval in between. In each session, a bolus of either hypertonic saline (6%, 0.1 mL, each), glutamate (0.1 mL, 0.5 M, each), or isotonic saline (0.9%, 0.1 mL, each) was randomly injected into a latent MTrP and a non-MTrP located in the right or left gastrocnemius medialis muscles. After each injection, participants were asked to rate the perceived pain intensity on an electronic visual analog scale (VAS) and to mark the pain areas on pain drawings. Maximal pain intensity (VASpeak), the area under the curve (VASauc), and local and referred pain areas were extracted. ResultsInjections of either hypertonic saline, glutamate, or isotonic saline into the latent MTrPs induced a higher VASpeak and larger VASauc than the non-MTrPs (all, P<0.05). Furthermore, the MTrPs with referred pain after painful injections were found to show higher VASpeak and larger VASauc than those without referred pain (both, P<0.001). ConclusionsThese results confirm the existence of nociceptive hypersensitivity at latent MTrPs and provide the first evidence that there exists non-nociceptive hypersensitivity (allodynia) at latent MTrPs. Finally, the occurrence of referred muscle pain is associated with higher pain sensitivity at latent MTrPs.

Attenuated skin blood flow response to nociceptive stimulation of latent myofascial trigger points.

OBJECTIVES To investigate the effect of painful stimulation of latent myofascial trigger points (MTrPs) on skin blood flow and to evaluate the relative sensitivity of laser Doppler flowmetry (LDF) and thermography in the measurement of skin blood flow. DESIGN Painful stimulation was obtained by a bolus injection of glutamate (0.1mL, 0.5M) into a latent MTrP located in the right or left brachioradialis muscles. A bolus of glutamate injection into a non-MTrP served as control. Pain intensity (visual analog scale [VAS]) was assessed after glutamate injection. Pressure pain threshold (PPT) was recorded bilaterally in the brachioradialis muscle before and after glutamate-induced pain. Skin blood flow and surface skin temperature were measured bilaterally in the forearms before, during, and after glutamate-induced pain with LDF and thermography. SETTING A biomedical research facility. PARTICIPANTS Fifteen healthy volunteer subjects. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES VAS, PPT, skin blood flow, and surface skin temperature. RESULTS Glutamate injection into latent MTrPs induced higher pain intensity (F=7.16; P<.05) and lower PPT (F=11.41, P<.005) than into non-MTrPs. Glutamate injection into non-MTrPs increased skin blood flow bilaterally in the forearms, but skin blood flow after glutamate injection into latent MTrPs was significantly less increased at the local injection area or decreased at distant areas compared with non-MTrPs (all P<.05). Skin temperature was not affected after glutamate injection into either latent MTrPs or non-MTrPs (all P>.05). CONCLUSIONS The present study demonstrated an attenuated skin blood flow response after painful stimulation of latent MTrPs compared with non-MTrPs, suggesting increased sympathetic vasoconstriction activity at latent MTrPs. Additionally, LDF was more sensitive than thermography in the detection of the changes in skin blood flow after intramuscular nociceptive stimulation.

A transient receptor potential vanilloid 4 contributes to mechanical allodynia following chronic compression of dorsal root ganglion in rats.

The aim of the present study was to investigate the role of transient receptor potential vanilloid 4 (TRPV4) in mediating mechanical allodynia in rodent models of chronic compression of the dorsal root ganglion (CCD). First, the levels of TRPV4 mRNA and protein expression in the dorsal root ganglion (DRG) were assessed using real-time RT-PCR and Western blotting analysis respectively at 7, 14, and 28 days post-CCD. Then, the effects of spinal administration of TRPV4 antisense oligodeoxynucleotide (ODN) and mismatch ODN on CCD-induced mechanical allodynia were evaluated. Lastly, the calcium responses to hypotonic solution and 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) were assessed following sham surgery, CCD, spinal application of TRPV4 antisense ODN and mismatch ODN. The results showed that the levels of TRPV4 mRNA and protein expression increased significantly at 7-28 days post-CCD when compared with the sham group, with the highest level at 7 days post-CCD. TRPV4 antisense ODN, but not mismatch ODN, partly reversed the CCD-induced mechanical allodynia. Additionally, TRPV4 antisense ODN had no effect on the baseline nociceptive response. The percentage of DRG neurons responsive to hypotonic solution and 4alpha-PDD and the fluorescence ratio of calcium response were also enhanced significantly in both the CCD group and the mismatch ODN group. These increased responses were significantly inhibited by TRPV4 antisense ODN. In conclusion, TRPV4 plays a crucial role in CCD-induced mechanical allodynia.

The Beneficial Effects of the Herbal Medicine Free and Easy Wanderer Plus (FEWP) and Fluoxetine on Post-Stroke Depression

OBJECTIVES Depression occurs frequently in post-stroke patients and appears to be associated with impairment of their rehabilitation and functional recovery. In this study, we evaluated the efficacy and tolerability of the herbal drug, Free and Easy Wanderer Plus (FEWP), in patients affected by post-stroke depression (PSD). METHODS One hundred fifty (150) moderately to severely depressed patients as determined by a score >20 on the Hamilton Depression Scale (HDS) after a single ischemic or hemorrhagic stroke were randomly divided into the FEWP group (n = 60), the fluoxetine group (n = 60), and the placebo group (n = 30). The FEWP, fluoxetine, and placebo were administered to the patients over a period of 8 weeks. Depression was evaluated by HDS and the Barthel Index (BI) before, during, and after the treatment. RESULTS Significantly higher clinical response rates were observed in both the FEWP and fluoxetine groups compared to the placebo group (60% and 65.5% versus 21.4%, chi(2) = 15.9, p < 0.01) and there was no difference in the response rates between the FEWP group and the fluoxetine group at the end of this study (60% versus 65.5%, chi(2) = 0.38, p > 0.05). Compared to fluoxetine, FEWP produced significantly greater improvement in depression at week 2 (15% versus 3.3%, chi(2) = 4.9, p < 0.05). Furthermore, FEWP produced significantly greater improvement in the activities of daily living (ADL) than fluoxetine at the end of this trial (BI: 43.8 +/- 5.6 versus 40.7 +/- 3.7, p < 0.01). CONCLUSIONS FEWP showed good efficacy, safety, and tolerability in PSD patients. We conclude that FEWP is well tolerated and may be a useful therapeutic option in patients with PSD.

Nuclear factor-kappa B mediates TRPV4-NO pathway involved in thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats

The aim of this study was to test the hypothesis that nuclear factor-kappa B (NF-κB) is involved in TRPV4-NO pathway in thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rat. Intrathecal administration of two NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC; 10(-1) to 10(-2)M) and BAY (100-50 μM), both induced significantly dose-dependent increase in the paw withdrawal latency (PWL) and decrease in nitric oxide (NO) content in DRG when compared with control rats. Pretreatment with 4α-phorbol 12,13-didecanoate (4α-PDD, transient receptor potential vanilloid 4 (TRPV4) synthetic activator, 1 nm) attenuated the suppressive effects of PDTC (10(-1)M) and BAY (100 μM) on CCD-induced thermal hyperalgesia and NO production. In addition, Western blot analysis indicated that CCD rats exhibited nuclear NF-κB protein expression and low levels of cytoplasmic inhibitory-kappa B (I-κB) expression; the increase in NF-κB expression and decrease in I-κB expression were reversed after intrathecal injection of PDTC. In conclusion, our data suggested that NF-κB could be involved in TRPV4-NO pathway in CCD-induced thermal hyperalgesia.

Spatial Pain Propagation Over Time Following Painful Glutamate Activation of Latent Myofascial Trigger Points in Humans

UNLABELLED The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. PERSPECTIVE This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation.

Ca2+ influx mediates the TRPV4–NO pathway in neuropathic hyperalgesia following chronic compression of the dorsal root ganglion

Chronic compression of the dorsal root ganglion (DRG) (CCD) in rats is a typical model of neuropathic pain. TRPV4 contributed to mechanical allodynia induced by the CCD model. Our previous study demonstrated that TRPV4 enhances neuropathic hyperalgesia through a NO-cGMP-PKG cascade. However, the underlying mechanism(s) is still largely unknown. Therefore, the aim of the present study was to test whether TRPV4-mediated Ca(2+) influx is involved in the TRPV4-NO pathway. Regulation of intracellular calcium concentration by intrathecal injection of TRPV4-targeted siRNA significantly decreased the behavioural hyperalgesia, NF-κB activity, and NO content in CCD rats. Intraperitoneal (i.p.) injection of mibefradil significantly induced dose-dependent increases in the paw withdrawal latency (PWL) and mechanical withdrawal thresholds (MWT), as well as decreases in NF-κB activity and NO content in DRG of CCD rats. Moreover, pre-treatment with 4α-PDD attenuated the suppressive effects of mibefradil on CCD-induced neuropathic hyperalgesia, NF-κB activity, and NO production. The data showed that TRPV4-mediated Ca(2+) influx might be engaged in the TRPV4-NO pathway in neuropathic hyperalgesia in the CCD model.

Effects of colchicine-induced microtubule depolymerization on TRPV4 in rats with chronic compression of the dorsal root ganglion.

The aim of this study was to investigate the effect of colchicine-induced microtubule depolymerization on allodynia in rats with chronic compression of the dorsal root ganglion (DRG) (CCD) and the effect of colchicine on transient receptor potential vanilloid 4 (TRPV4). Intrathecal administration of the anti-microtubule agent, colchicine, resulted in a dose-dependent and partial reduction in CCD-induced mechanical and thermal allodynia. The reduction of allodynia was associated with significant and dose-dependent decreases in the levels of both TRPV4 mRNA and protein expression in CCD rats. In addition, colchicine resulted in reduction and advance of TRPV4 currents in both DRG neurons and HEK293-TRPV4 cells. The current-voltage (IV) relation in HEK293-TRPV4 cells that were exposed to colchicine displayed a typical outward rectification characteristic of TRPV4 with the reversal potential shifted toward a more positive voltage. In conclusion, intrathecal administration of colchicine attenuated allodynia and TRPV4 contributed to the colchicine-induced attenuation of allodynia in CCD rats.

Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion.

The aim of this study was to investigate the relationships among TRPV4, p38, and neuropathic pain in a rat model of chronic compression of the dorsal root ganglion. Mechanical allodynia appeared after CCD surgery, enhanced via the intrathecal injection of 4α-phorbol 12,13-didecanoate (4α-PDD, an agonist of TRPV4) and anisomycin (an agonist of p38), but was suppressed by Ruthenium Red (RR, an inhibitor of TRPV4) and SB203580 (an inhibitor of p38). The protein expressions of p38 and P-p38 were upregulated by 4α-PDD and anisomycin injection but reduced by RR and SB203580. Moreover, TRPV4 was upregulated by 4α-PDD and SB203580 and downregulated by RR and anisomycin. In DRG tissues, the numbers of TRPV4- or p38-positive small neurons were significantly changed in CCD rats, increased by the agonists, and decreased by the inhibitors. The amplitudes of ectopic discharges were increased by 4α-PDD and anisomycin but decreased by RR and SB203580. Collectively, these results support the link between TRPV4 and p38 and their intermediary role for neuropathic pain in rats with chronic compression of the dorsal root ganglion.