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Aims/hypothesis Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes. Methods A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP−; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 μm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres. Results Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2–9.2) for healthy control participants; 6.2 (4.4–7.3) for DSP−; 1.3 (0.5–2.2) for painless DSP+; and 0.84 (0.4–1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p 1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration. Conclusions/interpretation In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes. Graphical abstract

Key Clinical Message Heparin‐induced thrombocytopenia (HIT) is a prothrombotic state that can affect patients with chronic kidney disease (CKD) on hemodialysis (HD). This case highlights the potential usefulness of apixaban therapy for patients with HIT and CKD on HD.

Background: \ud \ud Epidemiological studies in patients with neuropathic pain demonstrate a strong association with psychiatric conditions such as anxiety; however, the precipitating pathology between these symptoms remains unclear. To investigate this, we studied the effects of lifelong stress on levels of neuropathic pain–like behavior and conversely, the effects of chronic neuropathic injury on anxiety-like status in male and female mice. In addition, we assayed this link in painful and painless diabetic peripheral neuropathy patients.\ud \ud \ud Methods: \ud \ud Male and female mice were subject to ongoing life-stress or control living conditions. Baseline sensitivity and anxiety tests were measured followed by spared nerve injury (SNI) to the sciatic nerve. Subsequent sensory testing occurred until 3 weeks after SNI followed by anxiety tests between 4 and 6 weeks after SNI.\ud \ud \ud Results: \ud \ud Levels of tactile or cold allodynia did not differ between adult mice subject to lifelong chronic stress, relative to nonstressed controls, for at least 3 weeks after SNI. By contrast, longer-term neuropathic mice of both sexes displayed pronounced anxiety-like behavior, regardless of exposure to stress. If sex differences were present, females usually exhibited more pronounced anxiety-like behavior. These ongoing anxiety behaviors were corroborated with plasma corticosterone levels in distinct animal groups. In addition, data from patients with painful and nonpainful diabetic neuropathy showed a clear relationship between ongoing pain and anxiety, with females generally more affected than males.\ud \ud \ud Discussion: \ud \ud Taken together, these data demonstrate a strong link between chronic neuropathic pain and chronic anxiety, with the driver of this comorbidity being neuropathic pain as opposed to on-going stress.

Summary The spatial resolution of sensory systems is not homogeneous across their receptive surfaces. For example, tactile acuity is greatest on the fingertips, reflecting the high innervation density and small mechanoreceptive fields in this area [1, 2]. In contrast, pain is considered to lack any equivalent to the tactile fovea on the fingertips, where the density of nociceptive fibers is remarkably low [3]. Here, by combining psychophysics with histology, we show that this established notion is incorrect. By delivering small-diameter nociceptive-specific laser pulses to human volunteers, we discovered that (1) the spatial acuity for pain is higher on the fingertips than on proximal skin regions such as the hand dorsum, and (2) this distal-proximal gradient for pain is comparable to that for touch. In contrast, skin biopsies in the same participants showed that the intraepidermal nerve fiber density is lower in the fingertips than in the hand dorsum. The increased spatial acuity for pain on the fingertips therefore cannot be explained simply by peripheral innervation density. This finding is, however, consistent with the existence of fine-grained maps of nociceptive input to individual digits in the human primary somatosensory cortex [4]. Video Abstract, Highlights ► The spatial acuity for pain is higher on the fingertips than on the hand dorsum ► The density of nociceptive fibers is lower on the fingertips than on the dorsum ► The fovea at the fingertips is not explained by nociceptive innervation density

TOC summary Inherited neuropathies present with striking variety in their phenotype. We present a family with a myelin protein zero mutation and disabling neuropathic pain., We report an English kindred affected across 4 generations with a hereditary neuropathy associated with debilitating neuropathic pain as the main clinical feature. The principal finding on clinical examination was sensory loss, and there was variable motor dysfunction. Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range. There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero. This is predicted to lead to premature termination of translation. Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity. Chronic pain is an increasingly recognised sequela of certain hereditary neuropathies and may be musculoskeletal or neuropathic in origin. In this kindred, the neuropathy was relatively mild in severity, however, neuropathic pain was an important and disabling outcome.

Summary Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12–8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans. Video Abstract, Highlights ► We describe a novel human autosomal-dominant pain syndrome (FEPS) ► We demonstrate linkage of FEPS to a TRPA1 N855S point mutation ► FEPS patients show debilitating pain on fasting and physical stress ► N855S TRPA1 channels show enhanced inward currents but unaltered pharmacology

Purpose of review The current review provides a summary of recent advances in our understanding of the neuroimmune interactions which influence the development of pain associated with cancer. Recent findings Common signalling pathways, mediators and immune cell types are involved in the generation of pain as a result of both cancer and its treatment. Distinct alterations in central and peripheral neuronal function occur in multiple forms of cancer pain. Other more unusual neuroimmune processes such as graft-versus-host disease may cause cancer pain. Summary Identification of the cellular processes which underlie the generation of cancer pain provide potential novel targets for drug development and may eventually lead to improved pain management for cancer patients.

The α2δ-1 subunit of voltage-gated calcium channels is upregulated after sensory nerve injury and is also the therapeutic target of gabapentinoid drugs. It is therefore likely to play a key role in the development of neuropathic pain. In this study, we have examined mice in which α2δ-1 gene expression is disrupted, to determine whether α2δ-1 is involved in various modalities of nociception, and for the development of behavioral hypersensitivity after partial sciatic nerve ligation (PSNL). We find that naive α2δ-1−/−mice show a marked behavioral deficit in mechanical and cold sensitivity, but no change in thermal nociception threshold. The lower mechanical sensitivity is mirrored by a reducedin vivoelectrophysiological response of dorsal horn wide dynamic range neurons. The CaV2.2 level is reduced in brain and spinal cord synaptosomes from α2δ-1−/−mice, and α2δ-1−/−DRG neurons exhibit lower calcium channel current density. Furthermore, a significantly smaller number of DRG neurons respond to the TRPM8 agonist menthol. After PSNL, α2δ-1−/−mice show delayed mechanical hypersensitivity, which only develops at 11 d after surgery, whereas in wild-type littermates it is maximal at the earliest time point measured (3 d). There is no compensatory upregulation of α2δ-2 or α2δ-3 after PSNL in α2δ-1−/−mice, and other transcripts, including neuropeptide Y and activating transcription factor-3, are upregulated normally. Furthermore, the ability of pregabalin to alleviate mechanical hypersensitivity is lost in PSNL α2δ-1−/−mice. Thus, α2δ-1 is essential for rapid development of mechanical hypersensitivity in a nerve injury model of neuropathic pain.

We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype–phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM. Electronic supplementary material The online version of this article (doi:10.1007/s12017-012-8216-8) contains supplementary material, which is available to authorized users.

Summary Using a composite diagnostic-neuroimaging approach, this study shows the modulatory effects of pleasant cooling on pain-related cortical regions in a subject suffering from inherited erythromelalgia., We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Nav1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject.