Mechanical Stimulation Of Skin Research Articles

Involvement of interferon gamma signaling in spinal trigeminal caudal subnucleus astrocyte in orofacial neuropathic pain in rats with infraorbital nerve injury.

Background: Trigeminal nerve injury causes orofacial pain that can interfere with activities of daily life. However, the underlying mechanism remains unknown, and the appropriate treatment has not been established yet. This study aimed to examine the involvement of interferon gamma (IFN-γ) signaling in the spinal trigeminal caudal subnucleus (Vc) in orofacial neuropathic pain. Methods: Infraorbital nerve (ION) injury (IONI) was performed in rats by partial ION ligation. The head-withdrawal reflex threshold (HWT) to mechanical stimulation of the whisker pad skin was measured in IONI or sham rats, as well as following a continuous intracisterna magna administration of IFN-γ and a mixture of IFN-γ and fluorocitrate (inhibitor of astrocytes activation) in naïve rats, or an IFN-γ antagonist in IONI rats. The IFN-γ receptor immunohistochemistry and IFN-γ Western blotting were analyzed in the Vc after IONI or sham treatment. The glial fibrillary acid protein (GFAP) immunohistochemistry and Western blotting were also analyzed after administration of IFN-γ and the mixture of IFN-γ and fluorocitrate. Moreover, the change in single neuronal activity in the Vc was examined in the IONI, sham, and IONI group administered IFN-γ antagonist. Results: The HWT decreased after IONI. The IFN-γ and IFN-γ receptor were upregulated after IONI, and the IFN-γ receptor was expressed in Vc astrocytes. IFN-γ administration decreased the HWT, whereas the mixture of IFN-γ and fluorocitrate recovered the decrement of HWT. IFN-γ administration upregulated GFAP expression, while the mixture of IFN-γ and fluorocitrate recovered the upregulation of GFAP expression. IONI significantly enhanced the neuronal activity of the mechanical-evoked responses, and administration of an IFN-γ antagonist significantly inhibited these enhancements. Conclusions: IFN-γ signaling through the receptor in astrocytes is a key mechanism underlying orofacial neuropathic pain associated with trigeminal nerve injury. These findings will aid in the development of therapeutics for orofacial neuropathic pain.

Effects of gentle mechanical skin stimulation on subjective symptoms and joint range of motions in people with chronic neck and shoulder discomfort

This study aimed to examine the efficacy of a 2-week self-administered gentle mechanical skin stimulation on chronic neck and shoulder discomfort. In participants (n = 12) with chronic neck and shoulder discomfort, subjective measures of pain sensation, discomfort, and difficulty in moving using a visual analog scale (VAS, 0–10) and objective measures of 12 different joint range of motions (ROMs) for the cervical and shoulder regions, using a digital goniometer, were collected before and after self-care with contact acupuncture, called microcones. The self-care for 2 weeks significantly (p < 0.001) decreased all VAS scores to 2.2–2.3 from baseline values of 6.0–7.4. Of the 12 ROMs tested, 8 were significantly increased (p < 0.013). This open-label study suggests the use of self-care with microcones in improving subjective symptoms and joint ROMs in people suffering from chronic neck and shoulder discomfort. However, a randomized, double-blind, controlled clinical trial is needed to further investigate the efficacy and safety of microcones.

Pathognomonic Hypersensitivity of the Oral Mucosa and Tongue Induced by Diabetes Mellitus Accompanied by Saliva Reduction in Rats.

To clarify the mechanisms of hypersensitivity and spontaneous pain in intraoral structures in rats with diabetes mellitus (DM) accompanied by reduced saliva. Adult male Sprague-Dawley rats received a single injection of streptozocin (50 mg/kg) to induce DM. Saliva volume, intraoral hypersensitivity to menthol and capsaicin solutions, and head-withdrawal thresholds (HWTs) to noxious heat and mechanical stimulation of the tongue and whisker pad were measured. On day 7 after streptozocin injection, rats with DM had a significantly reduced spontaneous saliva volume, polydipsia, capsaicin aversion of the intraoral mucosa, and a reduced HWT to noxious mechanical stimulation of the whisker pad skin. The HWT to noxious mechanical stimulation of the tongue reduced further on day 14 after streptozocin injection. These symptoms are similar to the orofacial and intraoral complaints of patients with DM. Meanwhile, reduction of HWT to noxious heat stimulation of the tongue and whisker pad were not observed. These results indicate that spontaneous intraoral mucosal pain and mechanical facial hypersensitivity are antecedent symptoms before mechanical hypersensitivity of the tongue. The mechanisms of saliva reduction, spontaneous intraoral mucosa pain, and mechanical hypersensitivity of intraoral and facial structures induced by DM involve both peripheral and autonomic neuropathies. Tongue hypersensitivity to noxious mechanical stimulation might be aggravated by xerostomia.

A cutaneous mechanoneural interface for neuroprosthetic feedback.

Amputation destroys sensory end organs and does not provide an anatomical interface for cutaneous neuroprosthetic feedback. Here, we report the design and a biomechanical and electrophysiological evaluation of the cutaneous mechanoneural interface consisting of an afferent neural system that comprises a muscle actuator coupled to a natively pedicled skin flap in a cuff-like architecture. Muscle is actuated through electrical stimulation to induce strains or oscillatory vibrations on the skin flap that are proportional to a desired contact duration or contact pressure. In rat hindlimbs, the mechanoneural interface elicited native dermal mechanotransducers to generate at least four levels of graded contact and eight distinct vibratory afferents that were not significantly different from analogous mechanical stimulation of intact skin. The application of different patterns of electrical stimulation independently engaged slowly adapting and rapidly adapting mechanotransducers, and recreated an array of cutaneous sensations. The cutaneous mechanoneural interface can be integrated with current prosthetic technologies for tactile feedback.

Effect of anodal high-definition transcranial direct current stimulation on the pain sensitivity in a healthy population: a double-blind, sham-controlled study.

High-definition transcranial direct current stimulation (HD-tDCS) of brain areas related to pain processing may provide analgesic effects evident in the sensory detection and pain thresholds. The somatosensory sensitivity was assessed after HD-tDCS targeting the primary motor cortex (M1) and/or the dorsolateral prefrontal cortex (DLPFC). Eighty-one (40 females) subjects were randomly assigned to 1 of 4 anodal HD-tDCS protocols (20 minutes) applied on 3 consecutive days: Sham-tDCS, DLPFC-tDCS, M1-tDCS, and DLPFC&M1-tDCS (simultaneous transcranial direct current stimulation [tDCS] of DLPFC and M1). Subjects and experimenter were blinded to the tDCS protocols. The somatosensory sensitivity were assessed each day, before and after each tDCS by detection and pain thresholds to thermal and mechanical skin stimulation, vibration detection thresholds, and pressure pain thresholds. Subjects were effectively blinded to the protocol, with no significant difference in rates of whether they received real or placebo tDCS between the 4 groups. Compared with the Sham-tDCS, none of the active HD-tDCS protocols caused significant changes in detection or pain thresholds. Independent of tDCS protocols, pain and detection thresholds except vibration detection were increased immediately after the first tDCS protocol compared with baseline (P < 0.05). Overall, the active stimulation protocols were not able to induce significant modulation of the somatosensory thresholds in this healthy population compared with sham-tDCS. Unrelated to the HD-tDCS protocol, a decreased sensitivity was found after the first intervention, indicating a placebo effect or possible habituation to the quantitative sensory testing assessments. These findings add to the increasing literature of null findings in the modulatory effects of HD-tDCS on the healthy somatosensory system.

Oxytocin-Dependent Regulation of TRPs Expression in Trigeminal Ganglion Neurons Attenuates Orofacial Neuropathic Pain Following Infraorbital Nerve Injury in Rats.

We evaluated the mechanisms underlying the oxytocin (OXT)-induced analgesic effect on orofacial neuropathic pain following infraorbital nerve injury (IONI). IONI was established through tight ligation of one-third of the infraorbital nerve thickness. Subsequently, the head withdrawal threshold for mechanical stimulation (MHWT) of the whisker pad skin was measured using a von Frey filament. Trigeminal ganglion (TG) neurons innervating the whisker pad skin were identified using a retrograde labeling technique. OXT receptor-immunoreactive (IR), transient receptor potential vanilloid 1 (TRPV1)-IR, and TRPV4-IR TG neurons innervating the whisker pad skin were examined on post-IONI day 5. The MHWT remarkably decreased from post-IONI day 1 onward. OXT application to the nerve-injured site attenuated the decrease in MHWT from day 5 onward. TRPV1 or TRPV4 antagonism significantly suppressed the decrement of MHWT following IONI. OXT receptors were expressed in the uninjured and Fluoro-Gold (FG)-labeled TG neurons. Furthermore, there was an increase in the number of FG-labeled TRPV1-IR and TRPV4-IR TG neurons, which was inhibited by administering OXT. This inhibition was suppressed by co-administration with an OXT receptor antagonist. These findings suggest that OXT application inhibits the increase in TRPV1-IR and TRPV4-IR TG neurons innervating the whisker pad skin, which attenuates post-IONI orofacial mechanical allodynia.

Sensory Feedback in Upper Limb Prostheses

Abstract Loss of an arm is a devastating condition that can cross all socioeconomic groups. A major step forward in rehabilitation of amputees has been the development of myoelectric prostheses. Current robotic arms allow voluntary movements by using residual muscle contraction. However, a significant issue is lack of movement control and sensory feedback. These factors play an important role in integration and embodiment of a robotic arm. Without feedback, users rely on visual cues and experience overwhelming cognitive demand that results in poorer use of a prosthesis. The complexity of the afferent system presents a great challenge of creating a closed-loop hand prosthesis. Several groups have shown progress providing sensory feedback for upper limb amputees using robotic arms. Feedback, although still limited, is achieved through direct implantation of intraneural electrodes as well as through non-invasive methods. Moreover, evidence shows that over time some amputees develop a phantom sensation of the missing limb on their stump. This phenomenon can occur spontaneously as well as after non-invasive nerve stimulation, suggesting the possibility of recreating a sensory homunculus of the hand on the stump. Furthermore, virtual reality simulation in combination with mechanical stimulation of skin could augment the sensation phenomenon, leading to better interface between human and robotic arms.

Cinnamaldehyde elicits itch behavior via TRPV1 and TRPV4 but not TRPA1.

Introduction:Cinnamaldehyde (CA) elicits itch sensation in humans. We investigated if CA elicits scratching behavior in mice and determined the roles for TRPV1, TRPA1, and TRPV4.Materials and Methods:Scratching behavior elicited by intradermal injection of CA was assessed in wildtype (WT) mice and knockout (KO) mice lacking TRPV1, TRPA1, TRPV4, or deficient in mast cells. We also assessed scratching and wet dog shakes elicited by low-threshold mechanical stimulation of skin treated topically with CA or vehicle. Using calcium imaging we tested if CA activates dorsal root ganglion (DRG) neurons of each genotype.Results:Intradermal cheek injection of CA elicited dose-dependent hindlimb scratch bouts, with fewer forelimb wipes and facial groom bouts that were not dose-dependent. CA elicited significantly fewer scratch bouts in TRPV1 and TRPV4 KO mice, but not TRPA1KOs, compared with WTs. There were no sex differences across genotypes. The histamine H1 antagonist cetirizine did not affect CA-evoked scratching, which was normal in mast cell deficient mice, indicating lack of histamine involvement. Scores for alloknesis were significantly greater following topical application of CA compared with vehicle. Post-CA alloknesis scores were significantly higher in TRPV4KOs of both sexes and in female TRPV1 and TRPA1KOs, compared with WTs. Low threshold mechanical stimuli also elicited significantly more wet dog shakes in mice treated topically with 20% CA, with significantly fewer in TRPV1, TRPA1, and TRPV4KOs compared with WTs. In calcium imaging studies, CA excited 24% of WT DRG cells, significantly fewer (11.5%) in cells from TRPV4KOs, and none in TRPA1KOs. Responses of cells of all genotypes exhibited significant sensitization to repeated CA stimulation. Sensitization was significantly enhanced by IL-4, which itself excited 16% of WT DRG cells and none from TRPA1KOs.Discussion:The results indicate that TRPA1 is dispensable for CA-evoked scratching, which depends partly on TRPV1 and TRPV4.

Gentle Perineal Skin Stimulation for Control of Nocturia.

One of the major causes of nocturia is overactive bladder (OAB). Somatic afferent nerve stimuli are used for treating OAB. However, clinical evidence for the efficacy of this treatment is insufficient due to the lack of appropriate control stimuli. Studies on anesthetized animals, which eliminate emotional factors and placebo effects, have demonstrated an influence of somatic stimuli on urinary bladder functions and elucidated the underlying mechanisms. In general, the effects of somatic stimuli are dependent on the modality, location, and physical characteristics of the stimulus. Recently we showed that gentle stimuli applied to the perineal skin using a soft elastomer roller inhibited micturition contractions to a greater extent than a roller with a hard surface. Studies aiming to elucidate the neural mechanisms of gentle stimulation-induced inhibition reported that 1-10 Hz discharges of low-threshold cutaneous mechanoreceptive Aβ, Aδ, and C fibers evoked during stimulation with an elastomer roller inhibited the micturition reflex by activating the spinal cord opioid system, thereby reducing both ascending and descending transmission between bladder and pontine micturition center. The present review will provide a brief summary of (1) the effect of somatic electrical stimulation on the micturition reflex, (2) the effect of gentle mechanical skin stimulation on the micturition reflex, (3) the afferent, efferent, and central mechanisms underlying the effects of gentle stimulation, and (4) a translational clinical study demonstrating the efficacy of gentle skin stimuli for treating nocturia in the elderly with OAB by using the two roller types inducing distinct effects on rat micturition contractions. Anat Rec, 302:1824-1836, 2019. © 2019 American Association for Anatomy.

Central nervous system mechanisms involved in inhibition of micturition reflex by gentle mechanical skin stimulation

Central nervous system mechanisms involved in inhibition of micturition reflex by gentle mechanical skin stimulation

Quantitative Top-Down Mass Spectrometry Identifies Proteoforms Differentially Released during Mechanical Stimulation of Mouse Skin.

Mechanotransduction refers to the processes whereby mechanical stimuli are converted into electrochemical signals that allow for the sensation of our surrounding environment through touch. Despite its fundamental role in our daily lives, the molecular and cellular mechanisms of mechanotransduction are not yet well-defined. Previous data suggest that keratinocytes may release factors that activate or modulate cutaneous sensory neuron terminals, including small molecules, lipids, peptides, proteins, and oligosaccharides. This study presents a first step toward identifying soluble mediators of keratinocyte-sensory neuron communication by evaluating the potential for top-down mass spectrometry to identify proteoforms released during 1 min of mechanical stimulation of mouse skin from naı̈ve animals. Overall, this study identified 47 proteoforms in the secretome of mouse hind paw skin, of which 14 were differentially released during mechanical stimulation, and includes proteins with known and previously unknown relevance to mechanotransduction. Finally, this study outlines a bioinformatic workflow that merges output from two complementary analysis platforms for top-down data and demonstrates the utility of this workflow for integrating quantitative and qualitative data.

Age-Related Changes in Neuromodulatory Control of Bladder Micturition Contractions Originating in the Skin.

The brainstem is essential for producing micturition contractions of the urinary bladder. Afferent input from perineal skin evoked by gentle mechanical stimulation inhibits micturition contractions by decreasing both ascending and descending transmissions between the brainstem and spinal cord. Dysfunction of this inhibitory mechanism may be one cause of the increase in the prevalence of overactive bladder in old age. The aim of this study was to examine effect of aging on function of skin afferent fibers that inhibit bladder micturition contractions in rats. We used anesthetized male rats in three different age groups: young adult (4–5 months old), middle aged (6–9 months old), and aged (27–30 months old). The bladder was expanded to produce isovolumetric rhythmic micturition contractions. Skin afferent fibers were activated for 1 min either by electrical stimulation (0.5 ms, 0.2–10 V, 0.1–10 Hz) of the cutaneous branch of the pudendal nerve (CBPN) or by gentle mechanical skin stimulation with an elastomer roller. When skin afferent nerves were activated electrically, micturition contractions were inhibited in a similar manner in all age groups, with long latency inhibition induced by excitation of Aβ fibers and short latency inhibition by additional Aδ and C fiber excitation (at 1–10 Hz). On the contrary, when skin afferent nerves were activated mechanically by rolling, latency of inhibition following rolling stimulation was prolonged in aged rats. Single unitary afferent nerve activity of low-threshold mechanoreceptors (LTMs) from the cutaneous nerve was recorded. The discharge rate during rolling was not significantly reduced in Aβ units but was much lower in Aδ and C units in aged rats (0.4 and 0.5 Hz, respectively) than in young adult rats (3 and 7 Hz). These results suggest that the neural mechanism that inhibits bladder micturition contractions by skin afferent input is well maintained in old age, but the early inhibition by gentle skin stimulation is decreased because of reduced responses of Aδ- and C-LTMs.

Botulinum neurotoxin type A alleviates mechanical hypersensitivity associated with infraorbital nerve constriction injury in rats

We investigated the effect of botulinum neurotoxin type A (BoNT-A) on mechanical allodynia and hyperalgesia associated with infraorbital nerve constriction (ION-CCI) in rats. ION-CCI rats received a subcutaneous BoNT-A injection into the whisker pad area on day 7 postoperatively and underwent pain assessment on days 14 and 21 postoperatively. Rats were assigned to one of four treatment groups (n=5 each): ION-CCI+BoNT-A 20pg (low-dose group), ION-CCI+BoNT-A 200pg (high-dose group), ION-CCI+saline, and Sham. Mechanical allodynia and hyperalgesia were evaluated preoperatively (baseline) and on days 7, 14, and 21 postoperatively. After noxious mechanical stimulation of whisker pad skin, the number and distribution pattern of the phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) neurons were analyzed in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). On day 21, nocifensive behavior was attenuated by high-dose but not low-dose BoNT-A administration. In addition, after noxious mechanical stimulation of whisker pad skin, the numbers of pERK-IR cells in the superficial laminae of Vc and C1-C2 were significantly lower in the high-dose BoNT-A group than in the ION-CCI+saline group. The present findings suggest that, by suppressing Vc neuronal activity, high-dose intradermal injection of BoNT-A at the site of ION innervation alleviates mechanical facial allodynia and hyperalgesia associated with ION-CCI.

Gentle Mechanical Skin Stimulation Inhibits Micturition Contractions via the Spinal Opioidergic System and by Decreasing Both Ascending and Descending Transmissions of the Micturition Reflex in the Spinal Cord.

Recently, we found that gentle mechanical skin stimulation inhibits the micturition reflex in anesthetized rats. However, the central mechanisms underlying this inhibition have not been determined. This study aimed to clarify the central neural mechanisms underlying this inhibitory effect. In urethane-anesthetized rats, cutaneous stimuli were applied for 1 min to the skin of the perineum using an elastic polymer roller with a smooth, soft surface. Inhibition of rhythmic micturition contractions by perineal stimulation was abolished by naloxone, an antagonist of opioidergic receptors, administered into the intrathecal space of the lumbosacral spinal cord at doses of 2–20 μg but was not affected by the same doses of naloxone administered into the subarachnoid space of the cisterna magna. Next, we examined whether perineal rolling stimulation inhibited the descending and ascending limbs of the micturition reflex. Perineal rolling stimulation inhibited bladder contractions induced by electrical stimulation of the pontine micturition center (PMC) or the descending tract of the micturition reflex pathway. It also inhibited the bladder distension-induced increase in the blood flow of the dorsal cord at L5–S1, reflecting the neural activity of this area, as well as pelvic afferent-evoked field potentials in the dorsal commissure at the lumbosacral level; these areas contain long ascending neurons to the PMC. Neuronal activities in this center were also inhibited by the rolling stimulation. These results suggest that the perineal rolling stimulation activates the spinal opioidergic system and inhibits both ascending and descending transmissions of the micturition reflex pathway in the spinal cord. These inhibitions would lead to the shutting down of positive feedback between the bladder and the PMC, resulting in inhibition of the micturition reflex. Based on the central neural mechanisms we show here, gentle perineal stimulation may be applicable to several different types of overactive bladder.

An alternatively spliced IL-15 isoform modulates cell activation via inducing differential IL-15 receptor-dependent signaling pathways (CCR3P.203)

Abstract IL-15 is a pleiotropic cytokine mediating proliferation and survival of memory CD8+ T cells, natural killer (NK) and NKT cells as well as enhancing cytokine production. Deregulated and excessive expression of IL-15 has been implicated in promoting pathophysiologic state for human inflammatory diseases and malignant transformation. In a routine phenotype-driven screen, we identified a point mutation in exon 7 of the IL-15 gene in Pedigree 191 of N-ethyl-N-nitrosourea (ENU) mutagenized mice which expressed a depressed level of CD44 in CD8+ T cells (called DM for deficiency in memory) and resulted in an increased expression of alternatively spliced IL-15 isoform (IL-15ΔE7). Mechanical stimulation of DM skin reduced keratinocyte activation. Ectopic expression of IL-15ΔE7 in WT skin profoundly blocked neutrophil infiltration to inflamed skin induced by abrasion, sodium dodecyl sulfate or immiquimod treatment, suggesting a regulatory role of IL-15∆E7 in mediating proinflammatory response in skin. While treating T cells with recombinant soluble IL-15∆E7 protein activated a transient but delayed activation of MAPK/p38, IL-15∆E7 failed to activate phosphorylation of STAT5 and its downstream target bcl-2 expression. The capacity of IL-15ΔE7 in inducing differential signaling has pointed IL-15ΔE7 as a potential therapeutic agent for treating inflammatory disorders.

An Alternatively Spliced IL-15 Isoform Modulates Abrasion-Induced Keratinocyte Activation

In a routine phenotype-driven screen, we identified a point mutation in exon 7 of the IL-15 gene in Pedigree 191 (deficient memory (DM)) of N-ethyl-N-nitrosourea mutagenized mice. The DM epidermis expressed an alternatively spliced IL-15 mRNA isoform, IL-15ΔE7, and a wild-type (WT) IL-15 isoform at comparable levels. Mechanical stimulation of DM skin or DM skin graft transplanted onto the WT host resulted in reduced keratinocyte activation and inhibition of neutrophil infiltration into the dermis, demonstrating that DM keratinocytes produced less inflammatory response to external stimulation. Ectopic expression of IL-15ΔE7 in WT skin prevented abrasion-induced epidermal thickening, blocked the accumulation of nuclear antigen Ki67(+) cells in the basal and the suprabasal cell layers, increased loricrin expression, and also increased keratinocyte CXCL1 and G-CSF production. IL-15ΔE7 also profoundly blocked neutrophil infiltration in SDS- or immiquimod (IMQ)-treated WT skin. Recombinant IL-15ΔE7 failed to activate STAT-5 and its downstream target bcl-2 expression. Our study points to IL-15ΔE7 as a potential therapeutic agent for treating neutrophilia-associated inflammatory skin disorders.

Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection

In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons.The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment.These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at different time periods following IANX and resulting in the extraterritorial neuropathic pain in the orofacial region following trigeminal nerve injury.

Is An Acupuncture Point Identifiable with Skin Electrical Resistance Measurement?

One of the basic beliefs of traditional acupuncture is that needling and massaging on certain skin areas called acupuncture points (AP) help to treat medical conditions. While acupuncture is widely accepted as a useful non-pharmacological method for pain reduction, the mechanism of acupuncture is still debated—whether it works through the mechanical stimulation of skin and muscle nociceptors or through anatomically invisible APs and meridians. Some researchers have found that the electrical resistance of the skin over an AP is lower than that over a non-AP, and proposed the finding as indirect evidence of the existence of APs.1–6 However, the precision of skin electrical resistance measurement can be influenced by numerous factors such as dryness of skin, skin thickness, size of the sensing electrode, pressure applied on the electrode, inter-electrode distance, room temperature and humidity.7 Most of the previous studies on AP identification were done with the sensing electrode being stabilised by hand1–5; however, it is likely that small motions of the hand-held electrode could alter the reading of skin resistance and even bias the measurement. In the present investigation, the AP LI4 and an adjacent skin site were selected for …

Involvement of ERK phosphorylation of trigeminal spinal subnucleus caudalis neurons in thermal hypersensitivity in rats with infraorbital nerve injury.

To evaluate the involvement of the mitogen-activated protein kinase (MAPK) cascade in orofacial neuropathic pain mechanisms, this study assessed nocifensive behavior evoked by mechanical or thermal stimulation of the whisker pad skin, phosphorylation of extracellular signal-regulated kinase (ERK) in trigeminal spinal subnucleus caudalis (Vc) neurons, and Vc neuronal responses to mechanical or thermal stimulation of the whisker pad skin in rats with the chronic constriction nerve injury of the infraorbital nerve (ION-CCI). The mechanical and thermal nocifensive behavior was significantly enhanced on the side ipsilateral to the ION-CCI compared to the contralateral whisker pad or sham rats. ION-CCI rats had an increased number of phosphorylated ERK immunoreactive (pERK-IR) cells which also manifested NeuN-IR but not GFAP-IR and Iba1-IR, and were significantly more in ION-CCI rats compared with sham rats following noxious but not non-noxious mechanical stimulation. After intrathecal administration of the MEK1 inhibitor PD98059 in ION-CCI rats, the number of pERK-IR cells after noxious stimulation and the enhanced thermal nocifensive behavior but not the mechanical nocifensive behavior were significantly reduced in ION-CCI rats. The enhanced background activities, afterdischarges and responses of wide dynamic range neurons to noxious mechanical and thermal stimulation in ION-CCI rats were significantly depressed following i.t. administration of PD98059, whereas responses to non-noxious mechanical and thermal stimulation were not altered. The present findings suggest that pERK-IR neurons in the Vc play a pivotal role in the development of thermal hypersensitivity in the face following trigeminal nerve injury.

Expression of TRPV1 Channels after Nerve Injury Provides an Essential Delivery Tool for Neuropathic Pain Attenuation

Increased expression of the transient receptor potential vanilloid 1 (TRPV1) channels, following nerve injury, may facilitate the entry of QX-314 into nociceptive neurons in order to achieve effective and selective pain relief. In this study we hypothesized that the level of QX-314/capsaicin (QX-CAP) - induced blockade of nocifensive behavior could be used as an indirect in-vivo measurement of functional expression of TRPV1 channels. We used the QX-CAP combination to monitor the functional expression of TRPV1 in regenerated neurons after inferior alveolar nerve (IAN) transection in rats. We evaluated the effect of this combination on pain threshold at different time points after IAN transection by analyzing the escape thresholds to mechanical stimulation of lateral mental skin. At 2 weeks after IAN transection, there was no QX-CAP mediated block of mechanical hyperalgesia, implying that there was no functional expression of TRPV1 channels. These results were confirmed immunohistochemically by staining of regenerated trigeminal ganglion (TG) neurons. This suggests that TRPV1 channel expression is an essential necessity for the QX-CAP mediated blockade. Furthermore, we show that 3 and 4 weeks after IAN transection, application of QX-CAP produced a gradual increase in escape threshold, which paralleled the increased levels of TRPV1 channels that were detected in regenerated TG neurons. Immunohistochemical analysis also revealed that non-myelinated neurons regenerated slowly compared to myelinated neurons following IAN transection. We also show that TRPV1 expression shifted towards myelinated neurons. Our findings suggest that nerve injury modulates the TRPV1 expression pattern in regenerated neurons and that the effectiveness of QX-CAP induced blockade depends on the availability of functional TRPV1 receptors in regenerated neurons. The results of this study also suggest that the QX-CAP based approach can be used as a new behavioral tool to detect dynamic changes in TRPV1 expression, in various pathological conditions.