Keloid and hypertrophic scar: neurogenic inflammation hypotheses.

The mechanisms of fibroproliferation disease (FPD) of the skin, such as keloids and hypertrophic scars, are still unknown. Since mechanical stress appears to be an important factor for FPD generation, we have studied the intervening factors that connect mechanical stress with keloid and scar formation. Hence, we introduce our "neurogenic inflammation hypothesis" in this paper. Our hypothesis is as follows. Mechanical stress, including skin stretching, stimulates mechanosensitive nociceptors on sensory fibers in the skin. Stimulated fibers release neuropeptides, including SP and CGRP, and these peptides bind to the receptors SP-NK1R and CGRP-CGRP1R on various cells in the skin. Moreover, histamine release is upregulated by mast cells. Consequently, activated endothelial cells and vascular smooth muscle cells induce vasodilation and permeabilization of vessels. Cytokine production, including TGFbeta and NGF, is also stimulated by various cells. The neurogenic inflammation and upregulation of TGFbeta would activate fibroblasts through various signals. Interestingly, overexpressed NGF may induce the hyper-release of neuropeptides from sensory fibers, resulting in the accumulation of neuropeptides even in the absence of mechanical stress, once the malignant cycle has started. Moreover, individual differences in FPD generation may be based on differences in reactivity towards neuropeptides, NGF, and other neurotrophins. Hence, neuropeptide antagonists may be effective against FPD. While further experimental studies and clinical confirmation are needed, our hypothesis may provide new insights into the etiology and pathology of FPD of the skin, such as keloids and hypertrophic scars.

Static mechanical allodynia (SMA) is a paradoxical painful hypo-aesthesia: observations derived from neuropathic pain patients treated with somatosensory rehabilitation.

The present study aimed at investigating the time span it takes to remove a static mechanical allodynia (SMA) in humans suffering from chronic peripheral neuropathic pain. Forty-three subjects were included in the study and, during somatosensory rehabilitation, their SMA territory was precisely mapped. They then underwent distant vibrotactile counter stimulation (DVCS) treatment. It was observed that, with DVCS, SMA disappeared in all cases, and was transformed into an underlying hypoaesthesia. It was found that the "tenderness to touch" symptom (which is SMA) was located in the same territory as the underlying hypoaesthesia, which was located on a part of the cutaneous territory of a partially damaged nerve. These results demonstrate that treating patients suffering from neuropathic pain with DVCS revealed a skin territory of denervation that was previously masked by SMA. Thus, SMA can be considered as a paradoxical painful hypoaesthesia. Furthermore, mapping SMA is a valuable source of information for our understanding of abnormal sensory processing in neuropathic pain patients. We conclude that the mapping of the zone of hypersensitivity on the skin in humans suffering from chronic peripheral neuropathic pain improves diagnosis. The mapping of the zone of hypersensitivity is a tool to presume which branch of the peripheral nerve is damaged. The location of the axonal lesions is at the periphery, while the mechanism of pain sensitization is probably central and referred peripherally to the skin by a painful hypoaesthesia.

Cortical processing of respiratory afferent stimuli during sleep in children with the obstructive sleep apnea syndrome.

STUDY OBJECTIVES: Children with the obstructive sleep apnea syndrome (OSAS) have blunted upper airway responses to negative pressure, but the underlying cause remains unknown. Cortical processing of respiratory afferent information can be tested by measuring respiratory-related evoked potentials (RREPs). We hypothesized that children with OSAS have blunted RREP responses compared to normal children during sleep. DESIGN: During sleep, RREPs were obtained from EEG electrodes Fz, Cz, Pz during stage 2 sleep, slow wave sleep (SWS), and REM sleep. RREPs were produced with multiple short occlusions of the upper airway. SETTING: Sleep laboratory. PARTICIPANTS: 9 children with OSAS and 12 normal controls. MEASUREMENTS AND RESULTS: Children with OSAS had significantly decreased evoked K-complex production in stage 2 sleep and slow wave sleep and significantly reduced RREP N350 and P900 components in slow wave sleep. There were no significant differences in any of the measured RREP components in stage 2 sleep, and the only REM difference was decreased P2 amplitude. CONCLUSIONS: Results indicate that in children with OSAS, cortical processing of respiratory-related information measured with RREPs persists throughout sleep; however, RREPs during SWS are blunted compared to those seen in control children. Possible causes for this difference include a congenital deficit in neural processing reflective of a predisposition to develop OSAS, or changes in the upper airway rendering the airway less capable of transducing pressure changes following occlusion. Further research is required to evaluate RREPs after effective surgical treatment of OSAS in children, in order to distinguish between these alternatives.

Cyclooxygenase products sensitize muscle mechanoreceptors in humans with heart failure.

Prior work in animals and humans suggests that muscle mechanoreceptor control of sympathetic activation [muscle sympathetic nerve activity (MSNA)] during exercise in heart failure (HF) patients is heightened compared with that of healthy humans and that muscle mechanoreceptors are sensitized by metabolic by-products. We sought to determine whether cyclooxygenase products and/or endogenous adenosine, two metabolites of ischemic exercise, sensitize muscle mechanoreceptors during rhythmic handgrip (RHG) exercise in HF patients. Indomethacin, which inhibits the production of prostaglandins, and saline control were infused in 12 HF patients. In a different protocol, aminophylline, which inhibits adenosine receptors, and saline control were infused in 12 different HF patients. MSNA was recorded (microneurography). During exercise following saline, MSNA increased in the first minute of exercise, consistent with baseline heightened mechanoreceptor sensitivity. MSNA continued to increase during 3 min of RHG, indicative that muscle mechanoreceptors are sensitized by ischemia metabolites. Indomethacin, but not aminophylline, markedly attenuated the increase in MSNA during the entire 3 min of low-level rhythmic exercise, consistent with the sensitization of muscle mechanoreceptors by cyclooxygenase products. Interestingly, even the early increase in MSNA was abolished by indomethacin infusion, indicative of the very early generation of cyclooxygenase products after the onset of exercise in HF patients. In conclusion, muscle mechanoreceptors mediate the increase in MSNA during low-level RHG exercise in HF. Cyclooxygenase products, but not endogenous adenosine, play a central role in muscle mechanoreceptor sensitization. Finally, muscle mechanoreceptors in patients with HF have heightened basal sensitivity to mechanical stimuli, which also appears to be mediated by the early generation of cyclooxygenase products, resulting in exaggerated early increases in MSNA.

Characterization of sensory deficits in TrkB knockout mice.

The sensory deficit in TrkB deficient mice was evaluated by counting the neuronal loss in lumbar dorsal root ganglia (DRG), the absence of sensory receptors (cutaneous--associated to the hairy and glabrous skin - muscular and articular), and the percentage and size of the neurocalcin-positive DRG neurons (a calcium-binding protein which labels proprioceptive and mechanoceptive neurons). Mice lacking TrkB lost 32% of neurons, corresponding to the intermediate-sized and neurocalcin-positive ones. This neuronal lost was accomplished by the absence of Meissner corpuscles, and reduction of hair follicle-associated sensory nerve endings and Merkel cells. The mutation was without effect on Pacinian corpuscles, Golgi's organs and muscle spindles. Present results further characterize the sensory deficit of the TrkB-/- mice demonstrating that the intermediate-sized neurons in lumbar DRG, as well as the cutaneous rapidly and slowly adapting sensory receptors connected to them, are under the control of TrkB for survival and differentiation. This study might serve as a baseline for future studies in experimentally induced neuropathies affecting TrkB positive DRG neurons and their peripheral targets, and to use TrkB ligands in the treatment of neuropathies in which cutaneous mechanoreceptors are primarily involved.

Changes in synaptic effectiveness of myelinated joint afferents during capsaicin-induced inflammation of the footpad in the anesthetized cat.

The present series of experiments was designed to examine, in the anesthetized cat, the extent to which the synaptic efficacy of knee joint afferents is modified during the state of central sensitization produced by the injection of capsaicin into the hindlimb plantar cushion. We found that the intradermic injection of capsaicin increased the N2 and N3 components of the focal potentials produced by stimulation of intermediate and high threshold myelinated fibers in the posterior articular nerve (PAN), respectively. This facilitation lasted several hours, had about the same time course as the paw inflammation and was more evident for the N2 and N3 potentials recorded within the intermediate zone in the L6 than in the L7 spinal segments. The capsaicin-induced facilitation of the N2 focal potentials, which are assumed to be generated by activation of fibers signaling joint position, suggests that nociception may affect the processing of proprioceptive and somato-sensory information and, probably also, movement. In addition, the increased effectiveness of these afferents could activate, besides neurons in the intermediate region, neurons located in the more superficial layers of the dorsal horn. As a consequence, normal joint movements could produce pain representing a secondary hyperalgesia. The capsaicin-induced increased efficacy of the PAN afferents producing the N3 focal potentials, together with the reduced post-activation depression that follows high frequency autogenetic stimulation of these afferents, could further contribute to the pain sensation from non-inflamed joints during skin inflammation in humans. The persistence, after capsaicin, of the inhibitory effects produced by stimulation of cutaneous nerves innervating non-inflamed skin regions may account for the reported reduction of the articular pain sensations produced by trans-cutaneous stimulation.

Peripheral nerve injury-induced changes in spinal alpha(2)-adrenoceptor-mediated modulation of mechanically evoked dorsal horn neuronal responses.

UNLABELLED: Peripheral nerve injury has been associated with changes in the modulatory action of noradrenergic pathways on nociceptive traffic through the spinal cord. Thus, the purpose of this study was to assess whether endogenous noradrenergic descending inhibition, acting via spinal alpha(2)-receptors, is altered after peripheral nerve damage. We investigated the effects of spinal administration of a selective alpha(2)-adrenoceptor antagonist, atipamezole, on the evoked activity of deep dorsal horn neurons in animals with selective spinal nerve ligation (SNL) compared with a sham-operated group. Intrathecal administration of atipamezole (1, 10, and 100 microg) did not produce any significant effects on the electrically evoked neuronal responses in either animal group, with the exception of a small but significant enhancement of the postdischarge in the sham control group only. Similarly, no significant effects were observed with the heat-evoked neuronal responses in either group. Interestingly, atipamezole significantly increased the evoked responses of neurons to low-intensity mechanical stimuli in the sham control group but was without effect in the SNL group. Thus, our findings suggest that peripheral nerve injury can result in the suppression of noradrenergic spinal alpha(2)-adrenoceptor-mediated inhibition of spinal dorsal horn neuronal activity evoked by low-intensity mechanical stimuli. PERSPECTIVE: These results suggest that a tonically active noradrenergic inhibition of mechanically evoked spinal dorsal horn neuronal responses is lost after nerve injury. This shift in the balance of noradrenergic controls may be one of the many underlying mechanisms by which behavioral symptoms of hypersensitivity develop after nerve damage.

Identification of functional intramuscular rectal mechanoreceptors in aganglionic rectal smooth muscle from piebald lethal mice.

The mechanosensitive endings of low-threshold, slowly adapting pelvic afferents that innervate the rectum have been previously identified as rectal intraganglionic laminar endings (rIGLEs) that lie within myenteric ganglia. We tested whether the aganglionic rectum of piebald-lethal (s(l)/s(l)) mice lacks rIGLEs and whether this could explain impaired distension-evoked reflexes from this region. Extracellular recordings were made from fine rectal nerves in C57BL/6 wild-type and s(l)/s(l) mice, combined with anterograde labeling. In C57BL/6 mice, graded circumferential stretch applied to the rectum activated graded increases in firing of slowly adapting rectal mechanoreceptors. In s(l)/s(l) mice, graded stretch of the aganglionic rectum activated similar graded increases in rectal afferent firing. Stretch-sensitive afferents responded at low mechanical thresholds and fired more intensely at noxious levels of stretch. They could also be activated by probing their receptive fields with von Frey hairs and by muscle contraction. Anterograde labeling from recorded rectal nerves identified the mechanoreceptors of muscular afferents in the aganglionic rectal smooth muscle. A population of afferents were also recorded in both C57BL/6 and s(l)/s(l) mice that were activated by von Frey hair probing, but not stretch. In summary, the aganglionic rectum is innervated by a population of stretch-sensitive rectal afferent mechanoreceptor which develops and functions in the absence of any enteric ganglia. These results suggest that in patients with Hirschsprung's disease the inability to activate extrinsic distension reflexes from the aganglionic rectum is unlikely to be due to the absence of stretch-sensitive extrinsic mechanoreceptors.

Quantitative sensory measures distinguish office workers with varying levels of neck pain and disability.

This study was undertaken to investigate any relationship between sensory features and neck pain in female office workers using quantitative sensory measures to better understand neck pain in this group. Office workers who used a visual display monitor for more than four hours per day with varying levels of neck pain and disability were eligible for inclusion. There were 85 participants categorized according to their scores on the neck disability index (NDI): 33 with no pain (NDI<8); 38 with mild levels of pain and disability (NDI 9-29); 14 with moderate levels of pain (NDI30). A fourth group of women without neck pain (n=22) who did not work formed the control group. Measures included: thermal pain thresholds over the posterior cervical spine; pressure pain thresholds over the posterior neck, trapezius, levator scapulae and tibialis anterior muscles, and the median nerve trunk; sensitivity to vibrotactile stimulus over areas of the hand innervated by the median, ulnar and radial nerves; sympathetic vasoconstrictor response. All tests were conducted bilaterally. ANCOVA models were used to determine group differences between the means for each sensory measure. Office workers with greater self-reported neck pain demonstrated hyperalgesia to thermal stimuli over the neck, hyperalgesia to pressure stimulation over several sites tested; hypoaesthesia to vibration stimulation but no changes in the sympathetic vasoconstrictor response. There is evidence of multiple peripheral nerve dysfunction with widespread sensitivity most likely due to altered central nociceptive processing initiated and sustained by nociceptive input from the periphery.

Short-term sensitization of colon mechanoreceptors is associated with long-term hypersensitivity to colon distention in the mouse.

BACKGROUND & AIMS: Using a mouse model that reproduces major features of irritable bowel syndrome (long-lasting colon hypersensitivity without inflammation), we examined the contributions of 2 proteins, transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 3 (ASIC3), on development of behavioral hypersensitivity and assessed the function of colon mechanoreceptors of hypersensitive mice. METHODS: Visceral nociceptive behavior was measured as the visceromotor response (VMR) to colorectal distention (CRD) before and after intracolonic treatment with zymosan or saline. Colon pathology was assessed in parallel experiments by quantifying myeloperoxidase activity, intralumenal pH, and tissue histology. Electrophysiologic experiments were performed on naïve and zymosan-treated hypersensitive mice using an in vitro colon-pelvic nerve preparation. RESULTS: Zymosan, but not saline, produced significant and persistent increases in the VMRs of control mice; zymosan produced nonsignificant increases in the VMRs in TRPV1 and ASIC3 knockout mice. Colon myeloperoxidase activity and pH were unaffected by either CRD or intracolonic treatments. Pelvic nerve mechanoreceptors recorded from zymosan-treated or naïve mice had similar sensitivity to stretch of the colon. When applied acutely, zymosan sensitized muscular/mucosal mechanoreceptors in both naïve and hypersensitive mice. CONCLUSIONS: Zymosan produced sensitization of colon mechanoreceptors acutely in vitro and chronic (>or=7 weeks) behavioral hypersensitivity in the absence of inflammation. The behavioral hypersensitivity was partially dependent on both TRPV1 and ASIC3 because deletions of either of these genes blunted zymosan's effect, suggesting that these proteins may be important peripheral mediators for development of functional (ie, noninflammatory) visceral hypersensitivity.

Functional changes of the temporomandibular joint mechanoreceptors induced by a lateral mandibular shift in rats.

OBJECTIVE: To investigate changes in functional characteristics of the temporomandibular joint (TMJ) mechanoreceptors under mandibular lateral shift. MATERIALS AND METHODS: Forty 7-week-old male Wistar rats were divided into control and experimental groups. Rats in the experimental group received a modified guiding appliance (MGA) that was designed to shift the mandible to the left side in the occlusal position. Single-unit activities of the TMJ mechanoreceptors were evoked by indirect stimulation of passive jaw movement. Electrophysiologic recordings of TMJ units were obtained 1, 3, 5, 7, and 9 weeks after MGA setting from the gasserian ganglion. RESULTS: At 1 week after mandibular shift, the firing thresholds were the lowest and the maximum instantaneous frequencies were the highest in TMJ units. At 5 weeks, the firing thresholds in the nonshifted side were significantly lower than those in the shifted side. The maximum instantaneous frequencies in the nonshifted side were significantly higher than those in the shifted side at 1, 5, and 7 weeks. CONCLUSION: These results suggest that the functional lateral shift of the mandible could alter the response properties of TMJ mechanoreceptors, particularly on the nonshifted side.

The effect of low-dose insulin on mechanical sensitivity and allodynia in type I diabetes neuropathy.

The pathogenesis of diabetic neuropathy is multifactorial, but in general hyperglycemia through polyol and protein glycation pathways is considered to be a key etiological factor. Most likely insulin deficiency, in experimentally induced type I diabetes, contributes to the development of diabetes neuropathy. The aim of this study was to evaluate the in vivo behavioral effect of low-dose insulin on diabetic neuropathy in rats through behavioral testing in hyperglycemic conditions. Mechanical sensitivity and allodynia were tested in streptozotocin (STZ)-induced diabetic rats. After diabetes and neuropathy induction, treatment with low-dose insulin normalized behavioral test results in 37 days, while severe hyperglycemia persisted. Although this study provided no evidence about the role of hypoinsulinemia in the etiology of diabetes neuropathy, the results confirmed that an insulin deficit with impaired insulin signaling and neurotrophic support, rather than hyperglycemia, plays an essential role in the pathophysiology of painful diabetic neuropathy.

Method for detecting small changes in vibrotactile perception threshold related to tactile acuity.

Two metrics, expressing the change in mechanoreceptor-specific vibrotactile thresholds at a fingertip over a time interval of months or years, and the shift in threshold from the mean values recorded from the fingertips of healthy persons, have been constructed for thresholds measured from individual fingers. The metrics assume the applicability of the acute adaptation property of mechanoreceptors, which has been confirmed by thresholds obtained from 18 forest workers on two occasions, separated by 5 years. Hence, when expressed in decibels, both threshold changes and threshold shifts may be averaged at frequencies mediated by the same receptor population to improve precision. Differences between threshold changes at frequencies mediated by the same receptor population may be used to identify inconsistent subject performance, and hence potentially erroneous results. For this group of subjects, the threshold changes and threshold shifts at frequencies believed mediated by the slowly adapting type I (SAI) (4 and 6.3 Hz) and rapidly adapting type I (FAI) (20 and 32 Hz) receptors within each finger were correlated. In these circumstances, which may be expected to occur for some work-induced and systemic peripheral neuropathies, both threshold changes and threshold shifts may be summed over SAI and FAI receptors to improve precision, and hence the potential for interpretation.

Dyspnea: applying research to bedside practice.

Dyspnea is a common symptom in patients with acute and chronic critical illness as well as in patients receiving palliative care. While dyspnea can be found in a variety of clinical arenas and across many specialties, the mechanisms that cause dyspnea are similar. Although not often the cause for admission to critical care, it may complicate and extend length of stay. This article defines and describes dyspnea and its pathophysiology. Critical care nurses should strive to implement interventions supported by evidence whenever possible. An evidence-based plan of care for the assessment, planning, intervention, and evaluation of the patient with dyspnea is outlined, using levels of recommendation based on the strength of available evidence. Two case studies are presented to illustrate its application to clinical practice.

Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat.

Hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels contribute to rhythmic spontaneous activity in the heart and CNS. Ectopic spontaneous neuronal activity has been implicated in the development and maintenance of acute and chronic hyperalgesia, allodynia and spontaneous pain. Previously, we documented that systemic administration of ZD7288, a specific blocker of pacemaker current (I(h)), decreased ectopic activity in dorsal root ganglion (DRG) and reversed tactile allodynia in spinal nerve ligated (SNL) rats [Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM, Dubin AE (2003) Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J Neurosci 23:1169-1178]. Spontaneous pain is the chief clinical manifestation of peripheral nerve injury; however, a role for I(h) in spontaneous pain has not been described. Here, in further rat studies, we report that systemic administration of ZD7288 reversed spontaneous pain induced by mild thermal injury (MTI) and tactile allodynia induced by SNL and MTI. In contrast, ZD7288 did not reduce thermal hyperalgesia. An important locus of action appears to be in the skin since intraplantar (local) administration of ZD7288 completely suppressed tactile allodynia arising from MTI and SNL and reduced spontaneous pain due to MTI. Immunohistochemical staining of plantar skin sections detected HCN1-HCN4 expression in mechanosensory structures (e.g., Meissner's corpuscles and Merkel cells). Collectively, these data suggest that expression and modulation of I(h) in the peripheral nervous system, including specialized sensory structures, may play a significant role in sensory processing and contribute to spontaneous pain and tactile allodynia.