Lucy Gee

Keratinocyte expression of calcitonin gene-related peptide β: implications for neuropathic and inflammatory pain mechanisms.

Summary In a variety of chronic pain conditions, calcitonin gene‐related peptide (CGRP) is expressed at high levels in the skin, blood, and cerebrospinal fluid. Our results reveal that much of the increase may be due to the CGRPβ isoform made by epidermal keratinocytes, which express high levels of CGRP immunoreactivity in a variety of human and animal chronic pain conditions. ABSTRACT Calcitonin gene‐related peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebrospinal fluid (CSF) under a variety of inflammatory and chronic pain conditions, presumably derived from peptidergic C and Aδ innervation. Herein, CGRP immunolabeling (IL) was detected in epidermal keratinocytes at levels that were especially high and widespread in the skin of humans from locations afflicted with postherpetic neuralgia (PHN) and complex region pain syndrome type 1 (CRPS), of monkeys infected with simian immunodeficiency virus, and of rats subjected to L5/L6 spinal nerve ligation, sciatic nerve chronic constriction, and subcutaneous injection of complete Freund’s adjuvant. Increased CGRP‐IL was also detected in epidermal keratinocytes of transgenic mice with keratin‐14 promoter driven overexpression of noggin, an antagonist to BMP‐4 signaling. Transcriptome microarray, quantitative Polymerase Chain Reaction (qPCR), and Western blot analyses using laser‐captured mouse epidermis from transgenics, monolayer cultures of human and mouse keratinocytes, and multilayer human keratinocyte organotypic cultures, revealed that keratinocytes express predominantly the beta isoform of CGRP. Cutaneous peptidergic innervation has been shown to express predominantly the alpha isoform of CGRP. Keratinocytes also express the cognate CGRP receptor components, Calcitonin receptor‐like receptor (CRLR), Receptor activity‐modifying protein 1 (RAMP1), CGRP‐receptor component protein (RCP) consistent with known observations that CGRP promotes several functional changes in keratinocytes, including proliferation and cytokine production. Our results indicate that keratinocyte‐derived CGRPβ may modulate epidermal homeostasis through autocrine/paracrine signaling and may contribute to chronic pain under pathological conditions.

Structural and functional differences between neuropathy with and without pain

We aimed to find functional and structural differences in neuropathy between patients with and without chronic pain following nerve injury. We included 30 patients requiring hand surgery after a trauma, with 21 reporting chronic pain for more than one year after the injury, while 9 did not suffer from injury-related chronic pain. We assessed mechanical sensitivity, thermal thresholds, electrically induced pain and axon reflex erythema and cutaneous nerve fiber density in skin biopsies of the injured site and its contralateral control. Epidermal fiber density of the injured site was reduced similarly in both patient groups. Thresholds for cold and heat pain and axon reflex areas were reduced in the injured site, but did not differ between the patient groups. Only warmth thresholds were better preserved in the pain patients (35.2 vs. 38.4°C). Neuronal CGRP staining did not reveal any difference between pain and non-pain patients. Epidermal innervation density correlated best to warmth detection thresholds and deeper dermal innervation density to the area of the axon reflex erythema. No specific pattern of subjective, functional or structural parameters was detected that would separate the neuropathy patients into pain and non-pain patients. Specific staining of additional targets may help to improve our mechanistic understanding of pain development.

Unusual complications of deep brain stimulation

Deep brain stimulation (DBS) has emerged as a successful therapy for the treatment of several neurological disorders with potential implications in management of psychiatric disease. A variety of well-characterized hardware and surgical complications have been reported after the procedure, including postoperative hardware infection, system failure, and intracranial hemorrhage. Fortunately, serious surgical complications are rare, but they can lead to immediate or long-term disability. As the number of patients undergoing DBS continues to increase, newer and less common complications continue to emerge. It is imperative that clinicians become familiar with these complications in order to promptly recognize them and institute adequate early treatment. In this report, we examine the occurrence of unusual complications after DBS with emphasis on surgical, hardware, and stimulation-related complications.

The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDA-lesioned rats

Chronic pain is a major complaint for up to 85% of Parkinsons disease patients; however, it often not identified as a symptom of Parkinsons disease. Adequate treatment of motor symptoms often provides analgesic effects in Parkinsons patients but how this occurs remains unclear. Studies have shown both Parkinsons patients and 6‐hydroxydopamine‐lesioned rats exhibit decreased sensory thresholds. In humans, some show improvements in these deficits after subthalamic deep brain stimulation, while others report no change. Differing methods of testing and response criteria may explain these varying results. We examined this effect in 6‐hydroxydopamine‐lesioned rats. Sprague–Dawley rats were unilaterally implanted with subthalamic stimulating electrodes in the lesioned right hemisphere and sensory thresholds were tested using von Frey, tail‐flick and hot‐plate tests. Tests were done during and off subthalamic stimulation at 50 and 150 Hz to assess its effects on sensory thresholds. The 6‐hydroxydopamine‐lesioned animals exhibited lower mechanical (left paw, P < 0.01) and thermal thresholds than shams (hot plate, P < 0.05). Both 50 and 150 Hz increased mechanical (left paw; P < 0.01) and thermal thresholds in 6‐hydroxydopamine‐lesioned rats (hot‐plate test: 150 Hz, P < 0.05, 50 Hz, P < 0.01). Interestingly, during von Frey testing, low‐frequency stimulation provided a more robust improvement in some 6OHDA lesioned rats, while in others, the magnitude of improvement on high‐frequency stimulation was greater. This study shows that subthalamic deep brain stimulation improves mechanical allodynia and thermal hyperalgesia in 6‐hydroxydopamine‐lesioned animals at both high and low frequencies. Furthermore, we suggest considering using low‐frequency stimulation when treating Parkinsons patients where pain remains the predominant complaint.

Deep brain stimulation significantly decreases disability from low back pain in patients with advanced Parkinson's disease.

Background: Up to 60% of Parkinsons disease (PD) patients suffer from low back pain (LBP) during the course of their disease. How LBP affects daily functional status and how to manage this aspect of PD has not been adequately explored. Methods: We examined 16 patients undergoing bilateral subthalamic nucleus deep brain stimulation (STN DBS) who met the inclusion criteria for moderate disability from LBP, as classified by the Oswestry Low Back Pain Disability Index (OLBPD). Results: Thirteen of 16 patients had attempted additional treatments for LBP, including medical management, massage, chiropractic, epidural steroid injections and/or surgery, with minimal relief. Following DBS, there was a significant improvement in the OLBPD at both the 6-month and 1-year time points (p < 0.02, p < 0.005, respectively). A mean improvement of 31.7% on the OLBPD score was noted. The Visual Analogue Scale (VAS) similarly decreased significantly at 1 year (p = 0.015). There was no correlation between the OLBPD score and other measures, including the Unified Parkinsons Disease Rating Scale (UPDRS), age and other nonmotor symptoms. Conclusion: Given the prevalent yet undertreated disability associated with LBP in PD, these results are novel in that they show that STN DBS has a significant positive effect on disability associated with LBP.

Treatment of Allodynia by Occipital Nerve Stimulation in Chronic Migraine Rodent.

BACKGROUND Occipital nerve stimulation (ONS) is a therapy that benefits one-third of medically refractory chronic migraine (CM) patients. How ONS affects sensory thresholds and whether modulation of thresholds could predict which patients respond to the therapy remains unclear. OBJECTIVE To examine the effects of ONS on mechanical and thermal thresholds in a rodent CM model to better elucidate its mechanism of action. METHODS Male Sprague-Dawley rats were implanted bilaterally with electrodes to produce ONS. The CM cohort was infused with inflammatory media epidurally based on a validated model, whereas shams were not. Thresholds were evaluated with von Frey filaments and hot plate and thermode tests. RESULTS No baseline differences in sensory thresholds were found between the sham (n = 16) and CM (n = 16) groups. After headache induction, CM animals demonstrated mechanical allodynia in the occiput, periorbital region, forepaws, and hind paws (P < .05). In CM animals, ONS increased mechanical thresholds in all regions (P < .001), whereas in shams, it did not. ONS did not affect thermal thresholds in either group. CONCLUSION We show that ONS improves mechanical thresholds in a rodent CM model, but not in shams. Our finding that mechanical but not thermal thresholds are altered with ONS suggests a more significant modulation of A-α/β fibers than of C fibers. Assessing the ability of ONS to reduce mechanical thresholds during a trial period could potentially be used to predict which patients respond.

Supraspinal stimulation for treatment of refractory pain

Refractory pain syndromes often have far reaching effects and are quite a challenge for primary care providers and specialists alike to treat. With the help of site-specific neuromodulation and appropriate patient selection these difficult to treat pain syndromes may be managed. In this article, we focus on supraspinal stimulation (SSS) for treatment of intractable pain and discuss off-label uses of deep brain stimulation (DBS) and motor cortex stimulation (MCS) in context to emerging indications in neuromodulation. Consideration for neuromodulatory treatment begins with rigorous patient selection based on exhaustive conservative management, elimination of secondary gains, and a proper psychology evaluation. Trial stimulation prior to DBS is nearly always performed while trial stimulation prior to MCS surgery is symptom dependent. Overall, a review of the literature demonstrates that DBS should be considered for refractory conditions including nociceptive/neuropathic pain, phantom limb pain, and chronic cluster headache (CCH). MCS should be considered primarily for trigeminal neuropathic pain (TNP) and central pain. DBS outcome studies for post-stroke pain as well as MCS studies for complex regional pain syndrome (CRPS) show more modest results and are also discussed in detail.

Effect of low-frequency deep brain stimulation on sensory thresholds in Parkinson's disease

OBJECTIVE Chronic pain is a major distressing symptom of Parkinsons disease (PD) that is often undertreated. Subthalamic nucleus (STN) deep brain stimulation (DBS) delivers high-frequency stimulation (HFS) to patients with PD and has been effective in pain relief in a subset of these patients. However, up to 74% of patients develop new pain concerns while receiving STN DBS. Here the authors explore whether altering the frequency of STN DBS changes pain perception as measured through quantitative sensory testing (QST). METHODS Using QST, the authors measured thermal and mechanical detection and pain thresholds in 19 patients undergoing DBS via HFS, low-frequency stimulation (LFS), and off conditions in a randomized order. Testing was performed in the region of the body with the most pain and in the lower back in patients without chronic pain. RESULTS In the patients with chronic pain, LFS significantly reduced heat detection thresholds as compared with thresholds following HFS (p = 0.029) and in the off state (p = 0.010). Moreover, LFS resulted in increased detection thresholds for mechanical pressure (p = 0.020) and vibration (p = 0.040) compared with these thresholds following HFS. Neither LFS nor HFS led to changes in other mechanical thresholds. In patients without chronic pain, LFS significantly increased mechanical pain thresholds in response to the 40-g pinprick compared with thresholds following HFS (p = 0.032). CONCLUSIONS Recent literature has suggested that STN LFS can be useful in treating nonmotor symptoms of PD. Here the authors demonstrated that LFS modulates thermal and mechanical detection to a greater extent than HFS. Low-frequency stimulation is an innovative means of modulating chronic pain in PD patients receiving STN DBS. The authors suggest that STN LFS may be a future option to consider when treating Parkinsons patients in whom pain remains the predominant complaint.

353 High-Intensity Ultrasound for the Treatment of Vincristine-Induced Neuropathic Pain.

INTRODUCTION Vincristine is a commonly used chemotherapeutic agent but is associated with debilitating peripheral neuropathy that is often refractory to traditional medication. We explore 1 neuromodulatory option, high-intensity focused ultrasound (HIFU), which may work by altering neuronal activity. Thus, we focus on the efficacy of HIFU in treating vincristine-induced neuropathy (VIN) in the animal model. METHODS VIN rodents were created using a previously used animal model, and neuropathy was confirmed by mechanical and thermal testing using Von Frey Filaments (VFF), Randal-Selitto (RS), hot plate (HP), and tail-flick tests (TF). The VFF and RS tests are measures of innocuous and noxious mechanical thresholds, respectively, and the HP and TF are measures of paw and tail withdrawal times to thermal stimuli. These tests were performed before neuropathy induction, after a 2-week induction period, at 24 hours after HIFU and at 48 hours after HIFU. HIFU was applied to the L5 dorsal root ganglion of the left hind paw at 3 W for 2 minutes. RESULTS Although we only have 1 animal in our HIFU group thus far, our preliminary data suggest that HIFU increases mechanical and thermal thresholds compared with HIFU sham animals (n = 5). Specifically, innocuous and noxious mechanical thresholds were increased as measured with the VFF and RS tests, and thermal thresholds were also increased as measured by the HP test at 48 hours after HIFU application. Our HIFU animal did not exhibit increased TF thresholds. CONCLUSION Our preliminary data suggest that high-intensity ultrasound may be an effective way to increase mechanical and thermal thresholds in VIN.INTRODUCTION:Vincristine is a commonly used chemotherapeutic agent but is associated with debilitating peripheral neuropathy that is often refractory to traditional medication. We explore 1 neuromodulatory option, high-intensity focused ultrasound (HIFU), which may work by altering neuronal activity

The Effects of Mechanical and Thermal Stimuli on Local Field Potentials and Single Unit Activity in Parkinson's Disease Patients

Chronic pain is a major, debilitating symptom of Parkinsons disease (PD). Although, deep brain stimulation (DBS) has been shown to improve pain outcomes, the mechanisms underlying this phenomenon are unclear. Microelectrode recording allows us to measure both local field potentials (LFPs) and single neuronal unit activity (SUA).