Evaluation of outcome measures for post-operative dysphagia after anterior cervical discectomy and fusion.

PURPOSE: The goal is to conduct a review of the current literature to determine and evaluate the current classification metrics available for quantifying post-operative dysphagia. METHODS: We surveyed the literature for the subjective and objective measures used to classify dysphagia, and further described and analyzed them in the context of post-operative dysphagia (PD) after anterior cervical spine surgery, with a focus on anterior cervical discectomy and fusion (ACDF). We searched PubMed from the years 2005-2021 using the terms "anterior cervical discectomy and fusion" and "dysphagia or postoperative dysphagia." We included papers that were meta-analyses, systemic reviews, prospective, or retrospective studies. Our selection was further consolidated via abstract and title screening. Ultimately, nineteen articles were included and had full-text reviews. RESULTS: EAT-10 tool was shown to be more valid and reliable than the commonly used Bazaz grading system. HSS-DDI was found to have a high diagnostic accuracy in stratifying mild, moderate, and severe PD. A shortened 16-item version of the original 44-item SWAL-QOL was found to be statistically and clinically significant. When compared to PROMs, objective tests more accurately diagnose PD. CONCLUSION: We found that the most valuable subjective tests were the EAT-10 and HSS-DI because they are quick, sensitive, and correlated strongly with the well-established measurements of PD. The MBS and FEES provided accurate measurements of the severity of PD, but they required more time and equipment than the surveys. In some patient populations, such as those with pre-surgical dysphagia, objective testing should always be done.

Differential expression and pharmacology of native P2X receptors in rat and primate sensory neurons.

Evidence suggesting the involvement of P2X2 and P2X3 in chronic pain has been obtained mostly from rodent models. Here we show that rodents may be poor predictors of P2X3 pharmacology in human. We demonstrate that monkey and human dorsal root ganglion (DRG) neurons do not express appreciable levels of P2X2 subunit, contrary to rat sensory neurons. Additionally, we report functional P2X3 activity in monkey DRG neurons and confirm the absence of functional P2X2/3 receptors. Interestingly, native P2X3 receptors in rat and monkey DRGs show similar agonist potency, but different antagonist potencies for TNP-ATP [2-O-(2,4,6-trinitrophenyl)-ATP] and RO51. This unexpected difference in antagonist potency was confirmed by comparing rat and human P2X3 receptors in HEK293 cells. Mutagenesis studies reveal that two extracellular residues, A197 and T202, are synergistically responsible for the potency drop in primate P2X3 receptors. These results uncover species-specific P2X3 pharmacology and identify key mechanisms impacting the translatability of potential analgesics targeting P2X3 receptors.

Discovery of P2X3 selective antagonists for the treatment of chronic pain.

Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists.

Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain.

BACKGROUND: The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists. RESULTS: We provided evidence that dorsal root ganglia (DRG) cells harvested from CCI animals responded to stimulation by CCL2 with a concentration-dependent calcium rise involving PLC-dependent internal stores. This response was associated with an increase in evoked neuronal action potentials suggesting these cells were sensitive to CCR2 signalling. Importantly, treatment with AZ889 abolished CCL2-evoked excitation confirming that this activity is CCR2-mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. We next showed that in vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in CCI rats. Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. Furthermore, AZ889 abolished NMDA-dependent wind-up of spinal withdrawal reflex pathway in neuropathic animals giving insight into the spinal mechanism underlying the analgesic properties of AZ889. CONCLUSIONS: Overall, this study strengthens the important role of CCR2 in neuropathic pain and highlights feasibility that interfering on this mechanism at the spinal level with a selective antagonist can provide new analgesia opportunities.

Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes.

Diabetic neuropathy (DN) is a common severe complication of type 2 diabetes. The symptoms of chronic pain, tingling, and numbness are generally attributed to small fiber dysfunction. However, little is known about the pathology among innervation to distal extremities, where symptoms start earliest and are most severe, and where the innervation density is the highest and includes a wide variety of large fiber sensory endings. Our study assessed the immunochemistry, morphology, and density of the nonvascular innervation in glabrous skin from the hands of aged nondiabetic rhesus monkeys and from age-matched monkeys that had different durations of spontaneously occurring type 2 diabetes. Age-related reductions occurred among all types of innervation, with epidermal C-fiber endings preferentially diminishing earlier than presumptive Adelta-fiber endings. In diabetic monkeys epidermal innervation density diminished faster, became more unevenly distributed, and lost immunodetectable expression of calcitonin gene-related peptide and capsaicin receptors, TrpV1. Pacinian corpuscles also deteriorated. However, during the first few years of hyperglycemia, a surprising hypertrophy occurred among terminal arbors of remaining epidermal endings. Hypertrophy also occurred among Meissner corpuscles and Merkel endings supplied by Abeta fibers. After longer-term hyperglycemia, Meissner corpuscle hypertrophy declined but the number of corpuscles remained higher than in age-matched nondiabetics. However, the diabetic Meissner corpuscles had an abnormal structure and immunochemistry. In contrast, the expanded Merkel innervation was reduced to age-matched nondiabetic levels. These results indicate that transient phases of substantial innervation remodeling occur during the progression of diabetes, with differential increases and decreases occurring among the varieties of innervation.

Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome.

Complex regional pain syndromes (CRPS, type I and type II) are devastating conditions that can occur following soft tissue (CRPS type I) or nerve (CRPS type II) injury. CRPS type I, also known as reflex sympathetic dystrophy, presents in patients lacking a well-defined nerve lesion, and has been questioned as to whether or not it is a true neuropathic condition with an organic basis. As described here, glabrous and hairy skin samples from the amputated upper and lower extremity from two CRPS type I diagnosed patients were processed for double-label immunofluorescence using a battery of antibodies directed against neural-related proteins and mediators of nociceptive sensory function. In CRPS affected skin, several neuropathologic alterations were detected, including: (1) the presence of numerous abnormal thin caliber NF-positive/MBP-negative axons innervating hair follicles; (2) a decrease in epidermal, sweat gland, and vascular innervation; (3) a loss of CGRP expression on remaining innervation to vasculature and sweat glands; (4) an inappropriate expression of NPY on innervation to superficial arterioles and sweat glands; and (5) a loss of vascular endothelial integrity and extraordinary vascular hypertrophy. The results are evidence of widespread cutaneous neuropathologic changes. Importantly, in these CRPS type I patients, the myriad of clinical symptoms observed had detectable neuropathologic correlates.

ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons.

BACKGROUND: ASIC3, the most sensitive of the acid-sensing ion channels, depolarizes certain rat sensory neurons when lactic acid appears in the extracellular medium. Two functions have been proposed for it: 1) ASIC3 might trigger ischemic pain in heart and muscle; 2) it might contribute to some forms of touch mechanosensation. Here, we used immunocytochemistry, retrograde labelling, and electrophysiology to ask whether the distribution of ASIC3 in rat sensory neurons is consistent with either of these hypotheses. RESULTS: Less than half (40%) of dorsal root ganglion sensory neurons react with anti-ASIC3, and the population is heterogeneous. They vary widely in cell diameter and express different growth factor receptors: 68% express TrkA, the receptor for nerve growth factor, and 25% express TrkC, the NT3 growth factor receptor. Consistent with a role in muscle nociception, small (<25 microm) sensory neurons that innervate muscle are more likely to express ASIC3 than those that innervate skin (51% of small muscle afferents vs. 28% of small skin afferents). Over 80% of ASIC3+ muscle afferents co-express CGRP (a vasodilatory peptide). Remarkably few (9%) ASIC3+ cells express P2X3 receptors (an ATP-gated ion channel), whereas 31% express TRPV1 (the noxious heat and capsaicin-activated ion channel also known as VR1). ASIC3+/CGRP+ sensory nerve endings were observed on muscle arterioles, the blood vessels that control vascular resistance; like the cell bodies, the endings are P2X3- and can be TRPV1+. The TrkC+/ASIC3+ cell bodies are uniformly large, possibly consistent with non-nociceptive mechanosensation. They are not proprioceptors because they fail two other tests: ASIC3+ cells do not express parvalbumin and they are absent from the mesencephalic trigeminal nucleus. CONCLUSION: Our data indicates that: 1) ASIC3 is expressed in a restricted population of nociceptors and probably in some non-nociceptors; 2) co-expression of ASIC3 and CGRP, and the absence of P2X3, are distinguishing properties of a class of sensory neurons, some of which innervate blood vessels. We suggest that these latter afferents may be muscle metaboreceptors, neurons that sense the metabolic state of muscle and can trigger pain when there is insufficient oxygen.

Paucity of presumptive ruffini corpuscles in the index finger pad of humans.

Classically recognized as the cutaneous stretch receptors associated with the slowly adapting type II (SAII) primary afferents, Ruffini corpuscles have rarely been reported in the skin, despite numerous histologic investigations. Electrophysiological recordings of the primary afferents in humans suggest that SAII fibers represent approximately 15% of the myelinated mechanosensitive axons in the peripheral nerves innervating the volar surface of the hand. In the present study, an analysis of glabrous skin was conducted in human donors to assess the distribution of Ruffini and Ruffini-like corpuscles in the distal phalanx of the index finger. Only one presumptive Ruffini corpuscle was found in the skin processed for double immunofluorescence labeling with antibodies against protein gene product 9.5 and neurofilament 200-kDa subunit. Based on their relatively scattered distributions, we conclude that very few SAII primary afferents are likely to terminate as Ruffini corpuscles in human glabrous skin.

Distribution and terminal arborizations of cutaneous mechanoreceptors in the glabrous finger pads of the monkey.

Recent electrophysiological studies demonstrated that neurons in the somatosensory cortex of monkeys respond to tangential forces applied to glabrous skin. To unravel the peripheral basis for this cortical response, we determined the distribution of presumptive low-threshold mechanoreceptors innervating the distal finger pads of monkeys. Endings were reconstructed in immunolabeled serial sections imaged by epifluorescence and confocal microscopy. Although classically implicated as cutaneous stretch receptors, no Ruffini corpuscles were found in the glabrous skin. Ruffini-like endings were only detected at the base of the finger nails. Pacinian corpuscles were sparsely distributed in the deep dermis. Meissner corpuscles (MCs) in dermal papillary ridges had a comparably high density in the thumb, index, and fifth fingers. Each MC was innervated by several large-caliber axons. Within the limits of our reconstructions, some of these axons terminated in only one MC, whereas others innervated several MCs. Merkel endings covered about 80% of the base of the intermediate epidermal ridges that form the pattern of fingerprints. In some cases, the distal tip of a Merkel-related axon gave rise to a several terminal branches that supplied endings to tightly circumscribed (30-70 microm) clusters of Merkel cells. In other cases, the nodes of axons gave rise to en passant branches that formed extended chains of endings among Merkel cells spread over territories up to 300 microm long. Based on their relatively diffuse distributions, the axons that innervate multiple MCs or the axons with en passant Merkel terminations seem most suited to transduce tangential forces.

Multiple roles of transient receptor potential (TRP) channels in inflammatory conditions and current status of drug development.

During inflammation, several Transient Receptor Potential (TRP) channels are directly or indirectly activated by inflammatory signaling molecules and microenvironmental changes including heat, oxidative conditions or low pH. In either case, specific TRP isoforms participate in chains of pro- or anti-inflammatory signaling cascades often including activation of transcription factors, protein kinases and phospholipases, which result in signal integration or amplification. In a few cases, their potentials as therapeutic targets for inflammatory conditions like pruritis, cystitis, dermatitis, asthma among other conditions are investigated pre-clinically or clinically by pioneering academic groups and industries. Significant efforts are still devoted to the understanding of the detailed physiological roles played by TRP channels during inflammation. This review intends to summarize key biological findings and reports of drug discovery activities when available, in an overview of the current status and recent developments in the field.

Magnitude estimation of tangential force applied to the fingerpad.

Prior research on large-fibre skin mechanoreceptors in humans and monkeys has demonstrated their sensitivity to perpendicular skin indentation and to the rate of force application. Although some studies have examined skin afferent responses to stretch, relatively few investigations have examined the neural and perceptual correlates of shear forces applied tangentially to the skin. The present study assessed the ability of human subjects to scale different levels of tangential force applied to the distal pad of the index finger. Subjects were instructed to choose their own magnitude estimation scale. Seven force levels ranging from 0.15 to 0.70 N were delivered randomly at rates of 0.10 N/s, 0.15 N/s or 0.30 N/s. Tangential forces were produced with a smooth metal spatula coated with an adhesive to insure a shear force on the underlying skin without slip. The same procedures were also used to generate skin indentation with normal forces. The results showed that most human subjects were able to scale different magnitudes of both tangential and normal forces applied to the tip of the index finger. The rate of force change did not influence the perception of the applied forces. These results highlight the potentially important role of tangential forces in haptic perception.