Spinal interleukin-1ß induces mechanical spinal hyperexcitability in rats: Interactions and redundancies with TNF and IL-6.

Both spinal tumor necrosis factor (TNF) and interleukin-6 (IL-6) contribute to the development of "mechanical" spinal hyperexcitability in inflammatory pain states. Recently, we found that spinal sensitization by TNF was significantly reduced by blockade of spinal IL-6 signaling suggesting that IL-6 signaling is involved in spinal TNF effects. Here, we explored whether spinal interleukin-1ß (IL-1ß), also implicated in inflammatory pain, induces "mechanical" spinal hyperexcitability, and whether spinal IL-1ß effects are related to TNF and IL-6 effects. We recorded the responses of spinal cord neurons to mechanical stimulation of the knee joint in vivo and used cellular approaches on microglial and astroglial cell lines to identify interactions of IL-1ß, TNF, and IL-6. Spinal application of IL-1ß in anesthetized rats modestly enhanced responses of spinal cord neurons to innocuous and noxious mechanical joint stimulation. This effect was blocked by minocycline indicating microglia involvement, and significantly attenuated by interfering with IL-6 signaling. In the BV2 microglial cell line, IL-1ß, like TNF, enhanced the release of soluble IL-6 receptor, necessary for spinal IL-6 actions. Different to TNF, IL-1ß caused SNB-19 astrocytes to release interleukin-11. The generation of "mechanical" spinal hyperexcitability by IL-1ß was more pronounced upon spinal TNF neutralization with etanercept, suggesting that concomitant TNF limits IL-1ß effects. In BV2 cells, TNF stimulated the release of IL-1Ra, an endogenous IL-1ß antagonist. Thus, spinal IL-1ß has the potential to induce spinal hyperexcitability sharing with TNF dependency on IL-6 signaling, but TNF also limited IL-1ß effects explaining the modest effect of IL-1ß.

The cholinergic system in joint health and osteoarthritis: a narrative-review.

Osteoarthritis (OA) poses a major health and economic burden worldwide due to an increasing number of patients and the unavailability of disease-modifying drugs. In this review, the latest understanding of the involvement of the cholinergic system in joint homeostasis and OA will be outlined. First of all, the current evidence on the presence of the cholinergic system in the normal and OA joint will be described. Cholinergic innervation as well as the non-neuronal cholinergic system are detected. In a variety of inflammatory diseases, the classic cholinergic anti-inflammatory pathway lately received a lot of attention as via this pathway cholinergic agonists can reduce inflammation. The role of this cholinergic anti-inflammatory pathway in the context of OA will be discussed. Activation of this pathway improved the progression of the disease. Secondly, chondrocyte hypertrophy plays a pivotal role in osteophyte formation and OA development; the impact of the cholinergic system on hypertrophic chondroblasts and endochondral ossification will be evaluated. Cholinergic stimulation increased chondrocyte proliferation, delayed chondrocyte differentiation and caused early mineralisation. Moreover, acetylcholinesterase and butyrylcholinesterase affect the endochondral ossification via an acetylcholine-independent pathway. Thirdly, subchondral bone is critical for cartilage homeostasis and metabolism; the cholinergic system in subchondral bone homeostasis and disorders will be explored. An increase in osteoblast proliferation and osteoclast apoptosis is observed. Lastly, current therapeutic strategies for OA are limited to symptom relief; here the impact of smoking on disease progression and the potential of acetylcholinesterase inhibitors as candidate disease-modifying drug for OA will be discussed.

The Effects of Mechanical Scale on Neural Control and the Regulation of Joint Stability.

Recent work has demonstrated how the size of an animal can affect neural control strategies, showing that passive viscoelastic limb properties have a significant role in determining limb movements in small animals but are less important in large animals. We extend that work to consider effects of mechanical scaling on the maintenance of joint integrity; i.e., the prevention of aberrant contact forces within joints that might lead to joint dislocation or cartilage degradation. We first performed a literature review to evaluate how properties of ligaments responsible for joint integrity scale with animal size. Although we found that the cross-sectional area of the anterior cruciate ligament generally scaled with animal size, as expected, the effects of scale on the ligament's mechanical properties were less clear, suggesting potential adaptations in passive contributions to the maintenance of joint integrity across species. We then analyzed how the neural control of joint stability is altered by body scale. We show how neural control strategies change across mechanical scales, how this scaling is affected by passive muscle properties and the cost function used to specify muscle activations, and the consequences of scaling on internal joint contact forces. This work provides insights into how scale affects the regulation of joint integrity by both passive and active processes and provides directions for studies examining how this regulation might be accomplished by neural systems.

Startle evokes nearly identical movements in multi-jointed, two-dimensional reaching tasks.

StartReact is the ability of the startle reflex to involuntarily release a planned movement in the presence of a loud acoustic stimulus resulting in muscle activity patterns and kinematics that are tightly regulated and scaled with the intended action. Previous studies demonstrated startReact's robustness during simple single-joint reaching tasks and found no difference between startReact and voluntary movements for movement kinematics and muscle activation patterns. However, startReact has not been evaluated during multi-joint reaching movements with multiple degrees of freedom. It is unclear if startReact would evoke accurate and precise multi-joint reaching movements in an unrestricted workspace. Furthermore, if tested more rigorously, multi-joint startReact movement kinematics and muscle activation patterns might not be truly equivalent despite showing no difference through traditional ANOVAs. A previous study found multi-joint startReact was possible during unrestricted elbow and shoulder movement when reaching to a forward target. Therefore, we hypothesized that startReact would evoke similar multi-joint reaching movements for movement accuracy and muscle activation patterns when compared to voluntary movements in a multi-directional workspace. Expanding upon the previous study, our study uses a larger workspace and fully evaluates movement kinematics and muscle activations patterns. Results confirmed our hypothesis and found startReact movements were readily evoked in all directions. StartReact responses presented stereotypically earlier muscle activation, but the relative timing of agonist/antagonist firing pairs between startReact and voluntary movements remained similar. Results demonstrate that startReact is robustly present and equivalent in multi-joint reaching tasks and has potential clinical use for evaluating healthy and impaired movement.

Mechanisms Underlying Bone and Joint Pain.

PURPOSE OF REVIEW: The goal of this review is to provide a broad overview of the current understanding of mechanisms underlying bone and joint pain. RECENT FINDINGS: Bone or joint pathology is generally accompanied by local release of pro-inflammatory cytokines, growth factors, and neurotransmitters that activate and sensitize sensory nerves resulting in an amplified pain signal. Modulation of the pain signal within the spinal cord and brain that result in net increased facilitation is proposed to contribute to the development of chronic pain. Great strides have been made in our understanding of mechanisms underlying bone and joint pain that will guide development of improved therapeutic options for these patients. Continued research is required for improved understanding of mechanistic differences driving different components of bone and/or joint pain such as movement related pain compared to persistent background pain. Advances will guide development of more individualized and comprehensive therapeutic options.

Nikolaus Rüdinger (1832-1896), His Description of Joint Innervation in 1857, and the History of Surgical Joint Denervation.

BACKGROUND: Selective joint denervation has become a reliable palliative treatment, especially for painful joints in the upper and lower extremity. METHODS: This article highlights the life and work of Nikolaus Rüdinger (1832-1896) who first described joint innervation which became the basis of later techniques of surgical joint denervation. The historical evolution of this method is outlined. RESULTS: Rüdinger made a unique career from apprentice barber to military surgeon and anatomy professor in Munich, Germany. His first description of articular innervation of temporomandibular, shoulder, elbow, wrist, finger, sacroiliac, hip, knee, ankle, foot, and toe joints in 1857 stimulated the subsequent history of surgical joint denervation. Comparing his investigations with modern joint denervation methods, developed by pioneers like Albrecht Wilhelm or A. Lee Dellon, shows his great exactitude and anatomical correspondence despite different current terminology. Clinical series of modern surgical joint denervations reveal success rates of up to 80% with reliable long-term results. CONCLUSION: The history of joint denervation with Rüdinger as its important protagonist offers inspiring insights into the evolution of surgical techniques and exemplifies the value of descriptive functional anatomy, even if surgical application may not have been realized until a century later.

The visual encoding of purely proprioceptive intermanual tasks is due to the need of transforming joint signals, not to their interhemispheric transfer.

To perform goal-oriented hand movement, humans combine multiple sensory signals (e.g., vision and proprioception) that can be encoded in various reference frames (body centered and/or exo-centered). In a previous study (Tagliabue M, McIntyre J. PLoS One 8: e68438, 2013), we showed that, when aligning a hand to a remembered target orientation, the brain encodes both target and response in visual space when the target is sensed by one hand and the response is performed by the other, even though both are sensed only through proprioception. Here we ask whether such visual encoding is due 1) to the necessity of transferring sensory information across the brain hemispheres, or 2) to the necessity, due to the arms' anatomical mirror symmetry, of transforming the joint signals of one limb into the reference frame of the other. To answer this question, we asked subjects to perform purely proprioceptive tasks in different conditions: Intra, the same arm sensing the target and performing the movement; Inter/Parallel, one arm sensing the target and the other reproducing its orientation; and Inter/Mirror, one arm sensing the target and the other mirroring its orientation. Performance was very similar between Intra and Inter/Mirror (conditions not requiring joint-signal transformations), while both differed from Inter/Parallel. Manipulation of the visual scene in a virtual reality paradigm showed visual encoding of proprioceptive information only in the latter condition. These results suggest that the visual encoding of purely proprioceptive tasks is not due to interhemispheric transfer of the proprioceptive information per se, but to the necessity of transforming joint signals between mirror-symmetric limbs.NEW & NOTEWORTHY Why does the brain encode goal-oriented, intermanual tasks in a visual space, even in the absence of visual feedback about the target and the hand? We show that the visual encoding is not due to the transfer of proprioceptive signals between brain hemispheres per se, but to the need, due to the mirror symmetry of the two limbs, of transforming joint angle signals of one arm in different joint signals of the other.

On identifying kinematic and muscle synergies: a comparison of matrix factorization methods using experimental data from the healthy population.

Human motor behavior is highly goal directed, requiring the central nervous system to coordinate different aspects of motion generation to achieve the motion goals. The concept of motor synergies provides an approach to quantify the covariation of joint motions and of muscle activations, i.e., elemental variables, during a task. To analyze goal-directed movements, factorization methods can be used to reduce the high dimensionality of these variables while accounting for much of the variance in large data sets. Three factorization methods considered in this paper are principal component analysis (PCA), nonnegative matrix factorization (NNMF), and independent component analysis (ICA). Bilateral human reaching data sets are used to compare the methods, and advantages of each are presented and discussed. PCA and NNMF had a comparable performance on both EMG and joint motion data and both outperformed ICA. However, NNMF's nonnegativity condition for activation of basis vectors is a useful attribute in identifying physiologically meaningful synergies, making it a more appealing method for future studies. A simulated data set is introduced to clarify the approaches and interpretation of the synergy structures returned by the three factorization methods. NEW & NOTEWORTHY: Literature on comparing factorization methods in identifying motor synergies using numerically generated, simulation, and muscle activation data from animal studies already exists. We present an empirical evaluation of the performance of three of these methods on muscle activation and joint angles data from human reaching motion: principal component analysis, nonnegative matrix factorization, and independent component analysis. Using numerical simulation, we also studied the meaning and differences in the synergy structures returned by each method. The results can be used to unify approaches in identifying and interpreting motor synergies.

Proximal-distal differences in movement smoothness reflect differences in biomechanics.

Smoothness is a hallmark of healthy movement. Past research indicates that smoothness may be a side product of a control strategy that minimizes error. However, this is not the only reason for smooth movements. Our musculoskeletal system itself contributes to movement smoothness: the mechanical impedance (inertia, damping, and stiffness) of our limbs and joints resists sudden change, resulting in a natural smoothing effect. How the biomechanics and neural control interact to result in an observed level of smoothness is not clear. The purpose of this study is to 1) characterize the smoothness of wrist rotations, 2) compare it with the smoothness of planar shoulder-elbow (reaching) movements, and 3) determine the cause of observed differences in smoothness. Ten healthy subjects performed wrist and reaching movements involving different targets, directions, and speeds. We found wrist movements to be significantly less smooth than reaching movements and to vary in smoothness with movement direction. To identify the causes underlying these observations, we tested a number of hypotheses involving differences in bandwidth, signal-dependent noise, speed, impedance anisotropy, and movement duration. Our simulations revealed that proximal-distal differences in smoothness reflect proximal-distal differences in biomechanics: the greater impedance of the shoulder-elbow filters neural noise more than the wrist. In contrast, differences in signal-dependent noise and speed were not sufficiently large to recreate the observed differences in smoothness. We also found that the variation in wrist movement smoothness with direction appear to be caused by, or at least correlated with, differences in movement duration, not impedance anisotropy.NEW & NOTEWORTHY This article presents the first thorough characterization of the smoothness of wrist rotations (flexion-extension and radial-ulnar deviation) and comparison with the smoothness of reaching (shoulder-elbow) movements. We found wrist rotations to be significantly less smooth than reaching movements and determined that this difference reflects proximal-distal differences in biomechanics: the greater impedance (inertia, damping, stiffness) of the shoulder-elbow filters noise in the command signal more than the impedance of the wrist.

Evaluating the contributions of muscle activity and joint kinematics to weight perception across multiple joints.

Perceived heaviness is clearly a function of muscle activity: objects feel heavy, in part because they are lifted with more force than lighter feeling objects. Recent research showed that participants scale their perceptions to the ratio of muscle activity to lift acceleration during elbow lifts (Waddell et al. J Exp Psychol Hum Percept Perform 42:363-374, 2016). The current study sought psychophysiological functions relating perceived heaviness to EMG and peak lift acceleration across multiple lifts employing different muscles as prime movers. Participants lifted objects with three arm lifts-shoulder, elbow, and wrist-and reported perceived heaviness. In each lift, EMG was recorded from the anterior deltoid, biceps brachii, and forearm flexors, and peak angular acceleration was recorded about each joint. The resulting psychophysiological functions revealed the hypothesized ratio of muscle activity to peak lift acceleration in all lifts. Principal component regressions showed that the EMG of the forearm flexors and peak acceleration of the lifting joint were most relevant for perceived heaviness. The special role of forearm flexors in perceiving heaviness across different lifts was interpreted in terms of the invariant structure of the inertia tensor about the wrist.

Bidirectional transfer between joint and individual actions in a task of discrete force production.

The present study examined bidirectional learning transfer between joint and individual actions involving discrete isometric force production with the right index finger. To examine the effects of practice of joint action on performance of the individual action, participants performed a pre-test (individual condition), practice blocks (joint condition), and a post-test (individual condition) (IJI task). To examine the effects of practice of the individual action on performance during the joint action, the participants performed a pre-test (joint condition), practice blocks (individual condition), and a post-test (joint condition) (JIJ task). Whereas one participant made pressing movements with a target peak force of 10% maximum voluntary contraction (MVC) in the individual condition, two participants produced the target force of the sum of 10% MVC produced by each of them in the joint condition. In both the IJI and JIJ tasks, absolute errors and standard deviations of peak force were smaller post-test than pre-test, indicating bidirectional transfer between individual and joint conditions for force accuracy and variability. Although the negative correlation between forces produced by two participants (complementary force production) became stronger with practice blocks in the IJI task, there was no difference between the pre- and post-tests for the negative correlation in the JIJ task. In the JIJ task, the decrease in force accuracy and variability during the individual action did not facilitate complementary force production during the joint action. This indicates that practice performed by two people is essential for complementary force production in joint action.

Eye-hand coordination during visuomotor adaptation: effects of hemispace and joint coordination.

We previously examined adaptive changes of eye-hand coordination during learning of a visuomotor rotation. Gazes during reaching movements were initially directed to a feedback cursor in early practice, but were gradually shifted toward the target with more practice, indicating an emerging gaze anchoring behavior. This adaptive pattern reflected a functional change of gaze control from exploring the cursor-hand relation to guiding the hand to the task goal. The present study further examined the effects of hemispace and joint coordination associated with target directions on this behavior. Young adults performed center-out reaching movements to four targets with their right hand on a horizontal digitizer, while looking at a rotated visual feedback cursor on a computer monitor. To examine the effect of hemispace related to visual stimuli, two out of the four targets were located in the ipsilateral workspace relative to the hand used, the other two in the contralateral workspace. To examine the effect of hemispace related to manual actions, two among the four targets were related to reaches made in the ipsilateral workspace, the other two to reaches made in the contralateral workspace. Furthermore, to examine the effect of the complexity of joint coordination, two among the four targets were reaches involving a direct path from the start to the target involving elbow movements (simple), whereas the other two targets were reaches involving both shoulder and elbow movements (complex). The results showed that the gaze anchoring behavior gradually emerged during practice for reaches made in all target directions. The speed of this change was affected mainly by the hemispace related to manual actions, whereas the other two effects were minimal. The gaze anchoring occurred faster for the ipsilateral reaches than for the contralateral reaches; gazes prior to the gaze anchoring were also directed less at the cursor vicinity but more at the mid-area between the starting point and the target. These results suggest that ipsilateral reaches result in a better predictability of the cursor-hand relation under the visuomotor rotation, thereby prompting an earlier functional change of gaze control through practice from a reactive to a predictive control.

A multi-joint model of quiet, upright stance accounts for the "uncontrolled manifold" structure of joint variance.

The upright body in quiet stance is usually modeled as a single-link inverted pendulum. This agrees with most of the relevant sensory organs being at the far end of the pendulum, i.e., the eyes and the vestibular system in the head. Movement of the body in quiet stance has often been explained in terms of the "ankle strategy," where most movement is generated by the ankle musculature, while more proximal muscle groups are only rarely activated for faster movements or in response to perturbations, for instance, by flexing at the hips in what has been called the "hip strategy." Recent empirical evidence, however, shows that instead of being negligible in quiet stance, the movement in the knee and hip joints is even larger on average than the movement in the ankle joints (J Neurophysiol 97:3024-3035, 2007). Moreover, there is a strong pattern of covariation between movements in the ankle, knee and hip joints in a way that most of the observed movements leave the anterior-posterior position of the whole-body center of mass (CoM) invariant, i.e., only change the configuration of the different body parts around the CoM, instead of moving the body as a whole. It is unknown, however, where this covariation between joint angles during quiet stance originates from. In this paper, we aim to answer this question using a comprehensive model of the biomechanical, muscular and neural dynamics of a quietly standing human. We explore four different possible feedback laws for the control of this multi-link pendulum in upright stance that map sensory data to motor commands. We perform simulation studies to compare the generated inter-joint covariance patterns with experimental data. We find that control laws that actively coordinate muscle activation between the different joints generate correct variance patterns, while control laws that control each joint separately do not. Different specific forms of this coordination are compatible with the data.

Intersegmental coordination elicited by unexpected multidirectional slipping-like perturbations resembles that adopted during steady locomotion.

This study aimed at testing the hypothesis that reactive biomechanical responses elicited by unexpected slipping-like perturbations delivered during steady walking are characterized by an intersegmental coordination strategy resembling that adopted during unperturbed walking. Fifteen healthy subjects were asked to manage multidirectional slipping-like perturbations delivered while they walked steadily. The planar covariation law of elevation angles related to lower limb segments was the main observed variable related to unperturbed and perturbed strides. Principal component analysis was used to verify whether elevation angles covaried, both before and after the onset of the perturbation, and, if so, the orientation of the related planes of covariation was compared. Results revealed that the planar covariation law of the unperturbed limb after onset of the perturbation was systematically similar to that seen during steady walking. This occurred despite differences in range of motion and intersubject variability of both elevation and joint angles. The analysis strongly corroborates the hypothesis that the planar covariation law emerges from the interaction between spinal neural networks and limb mechanical oscillators. In particular, fast and stereotyped reactive strategies may result from the interaction among activities of downstream neural networks encrypting well-trained motor schemes, such as those related to walking, limb dynamics, and sensory motor information gathered during the perturbation. In addition, our results allowed us to speculate that rehabilitative treatment based on unexpected perturbations and relying on the plasticity of the central nervous system may also be effective in eliciting unimpaired intralimb coordination in neurological patients.

A three-leg model producing tetrapod and tripod coordination patterns of ipsilateral legs in the stick insect.

Insect locomotion requires the precise coordination of the movement of all six legs. Detailed investigations have revealed that the movement of the legs is controlled by local dedicated neuronal networks, which interact to produce walking of the animal. The stick insect is well suited to experimental investigations aimed at understanding the mechanisms of insect locomotion. Beside the experimental approach, models have also been constructed to elucidate those mechanisms. Here, we describe a model that replicates both the tetrapod and tripod coordination pattern of three ipsilateral legs. The model is based on an earlier insect leg model, which includes the three main leg joints, three antagonistic muscle pairs, and their local neuronal control networks. These networks are coupled via angular signals to establish intraleg coordination of the three neuromuscular systems during locomotion. In the present three-leg model, we coupled three such leg models, representing front, middle, and hind leg, in this way. The coupling was between the levator-depressor local control networks of the three legs. The model could successfully simulate tetrapod and tripod coordination patterns, as well as the transition between them. The simulations showed that for the interleg coordination during tripod, the position signals of the levator-depressor neuromuscular systems sent between the legs were sufficient, while in tetrapod, additional information on the angular velocities in the same system was necessary, and together with the position information also sufficient. We therefore suggest that, during stepping, the connections between the levator-depressor neuromuscular systems of the different legs are of primary importance.

A dual-learning paradigm can simultaneously train multiple characteristics of walking.

Impairments in human motor patterns are complex: what is often observed as a single global deficit (e.g., limping when walking) is actually the sum of several distinct abnormalities. Motor adaptation can be useful to teach patients more normal motor patterns, yet conventional training paradigms focus on individual features of a movement, leaving others unaddressed. It is known that under certain conditions, distinct movement components can be simultaneously adapted without interference. These previous "dual-learning" studies focused solely on short, planar reaching movements, yet it is unknown whether these findings can generalize to a more complex behavior like walking. Here we asked whether a dual-learning paradigm, incorporating two distinct motor adaptation tasks, can be used to simultaneously train multiple components of the walking pattern. We developed a joint-angle learning task that provided biased visual feedback of sagittal joint angles to increase peak knee or hip flexion during the swing phase of walking. Healthy, young participants performed this task independently or concurrently with another locomotor adaptation task, split-belt treadmill adaptation, where subjects adapted their step length symmetry. We found that participants were able to successfully adapt both components of the walking pattern simultaneously, without interference, and at the same rate as adapting either component independently. This leads us to the interesting possibility that combining rehabilitation modalities within a single training session could be used to help alleviate multiple deficits at once in patients with complex gait impairments.

Maintaining balance against force perturbations: impaired mechanisms unresponsive to levodopa in Parkinson's disease.

There is evidence that postural instability associated with Parkinson's disease (PD) is not adequately improved by levodopa, implying involvement of nondopaminergic pathways. However, the mechanisms contributing to postural instability have yet to be fully identified and tested for their levodopa responsiveness. In this report we investigate balance processes that resist external forces to the body when standing. These include in-place responses and the transition to protective stepping. Forward and backward shoulder pulls were delivered using two force-feedback-controlled motors and were randomized for direction, magnitude, and onset. Sixteen patients with PD were tested OFF and ON levodopa, and 16 healthy controls were tested twice. Response behavior was quantified from 3-dimensional ground reaction forces and kinematic measurements of body segments and total body center-of-mass (CoM) motion. In-place responses resisting the pull were significantly smaller in PD as reflected in reduced horizontal anteroposterior ground reaction force and increased CoM displacement. Ankle, knee, and hip moments contributing to this resistance were smaller in PD, with the knee extensor moment to backward pulls being the most affected. The threshold force needed to evoke a step was also smaller for PD in the forward direction. Protective steps evoked by suprathreshold pulls showed deficits in PD in the backward direction, with steps being shorter and more steps being required to arrest the body. Levodopa administration had no significant effect on either in-place or protective stepping deficits. We conclude that processes employed to maintain balance in the face of external forces show impairment in PD consistent with disruption to nondopaminergic systems.

Characterization of cutaneous and articular sensory neurons.

BACKGROUND: A wide range of stimuli can activate sensory neurons and neurons innervating specific tissues often have distinct properties. Here, we used retrograde tracing to identify sensory neurons innervating the hind paw skin (cutaneous) and ankle/knee joints (articular), and combined immunohistochemistry and electrophysiology analysis to determine the neurochemical phenotype of cutaneous and articular neurons, as well as their electrical and chemical excitability. RESULTS: Immunohistochemistry analysis using RetroBeads as a retrograde tracer confirmed previous data that cutaneous and articular neurons are a mixture of myelinated and unmyelinated neurons, and the majority of both populations are peptidergic. In whole-cell patch-clamp recordings from cultured dorsal root ganglion neurons, voltage-gated inward currents and action potential parameters were largely similar between articular and cutaneous neurons, although cutaneous neuron action potentials had a longer half-peak duration (HPD). An assessment of chemical sensitivity showed that all neurons responded to a pH 5.0 solution, but that acid-sensing ion channel (ASIC) currents, determined by inhibition with the nonselective acid-sensing ion channel antagonist benzamil, were of a greater magnitude in cutaneous compared to articular neurons. Forty to fifty percent of cutaneous and articular neurons responded to capsaicin, cinnamaldehyde, and menthol, indicating similar expression levels of transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1), and transient receptor potential melastatin 8 (TRPM8), respectively. By contrast, significantly more articular neurons responded to ATP than cutaneous neurons. CONCLUSION: This work makes a detailed characterization of cutaneous and articular sensory neurons and highlights the importance of making recordings from identified neuronal populations: sensory neurons innervating different tissues have subtly different properties, possibly reflecting different functions.

Histaminergic Pharmacology Modulates the Analgesic and Antiedematogenic Effects of Spinally Injected Morphine.

BACKGROUND: Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine. METHODS: After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group. RESULTS: Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect. CONCLUSIONS: Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

Locomotor control of limb force switches from minimal intervention principle in early adaptation to noise reduction in late adaptation.

During movement, errors are typically corrected only if they hinder performance. Preferential correction of task-relevant deviations is described by the minimal intervention principle but has not been demonstrated in the joints during locomotor adaptation. We studied hopping as a tractable model of locomotor adaptation of the joints within the context of a limb-force-specific task space. Subjects hopped while adapting to shifted visual feedback that induced them to increase peak ground reaction force (GRF). We hypothesized subjects would preferentially reduce task-relevant joint torque deviations over task-irrelevant deviations to increase peak GRF. We employed a modified uncontrolled manifold analysis to quantify task-relevant and task-irrelevant joint torque deviations for each individual hop cycle. As would be expected by the explicit goal of the task, peak GRF errors decreased in early adaptation before reaching steady state during late adaptation. Interestingly, during the early adaptation performance improvement phase, subjects reduced GRF errors by decreasing only the task-relevant joint torque deviations. In contrast, during the late adaption performance maintenance phase, all torque deviations decreased in unison regardless of task relevance. In deadaptation, when the shift in visual feedback was removed, all torque deviations decreased in unison, possibly because performance improvement was too rapid to detect changes in only the task-relevant dimension. We conclude that limb force adaptation in hopping switches from a minimal intervention strategy during performance improvement to a noise reduction strategy during performance maintenance, which may represent a general control strategy for locomotor adaptation of limb force in other bouncing gaits, such as running.