Enhanced c-Fos expression in the central amygdala correlates with increased thigmotaxis in rats with peripheral nerve injury

Pain is associated with affective, cognitive and sensory dysfunction. Animal models can be used to observe ethologically relevant behaviours such as thigmotaxis, giving insight into how ongoing sensory abnormalities influence natural rodent behaviours. The amygdala is a complex group of nuclei implicated in the integration and generation of emotional behavioural responses, including those associated with pain, and a region known as the central amygdala is particularly associated with generation of behavioural responses, due to its links to the descending pain modulation pathways; as such, study of amygdalar c-Fos immunoreactivity can help identify the neuronal circuits involved.This study investigated changes in both nociceptive evoked responses and open field behaviour following spinal nerve transection (SNT) in male Wistar rats, and attempted to correlate these with changes in central amygdala c-Fos immunoreactivity.Fourteen days after SNT, mechanical hypersensitivity was present in the hind paw ipsilateral to site of injury. Thigmotactic behaviour was significantly increased in both SNT and sham surgery animals, with c-Fos immunoreactivity in the central amygdala significantly greater in SNT animals compared to both sham and naive groups. Activation was greatest in the capsular and lateral subnuclei of the central amygdala, and in the caudal-most regions. There was a strong correlation between thigmotactic behaviour and central amygdala activation following SNT surgery not seen in sham animals suggesting a role for the amygdala in behavioural responses to peripheral nerve injury.This study provides evidence to support the role of the amygdala in thigmotactic open field behaviour following SNT. WHAT DOES THIS STUDY ADD?: Thigmotaxis and amygdala activation are positively correlated in rats following spinal nerve transection. Behavioural changes seen in sham animals did not correlate with amygdala activation, suggesting amygdala activation is related to nociceptive input. Evoked measures, such as hindpaw withdrawal, are not correlated with either thigmotaxis or amygdala activation, emphasizing the importance of complex behaviours when studying pain

Is number sense impaired in chronic pain patients?

BACKGROUND: Recent advances in imaging have improved our understanding of the role of the brain in painful conditions. Discoveries of morphological changes have been made in patients with chronic pain, with little known about the functional consequences when they occur in areas associated with ‘number-sense’; thus, it can be hypothesized that chronic pain impairs this sense. METHODS: First, an audit of the use of numbers in gold-standard pain assessment tools in patients with acute and chronic pain was undertaken. Secondly, experiments were conducted with patients with acute and chronic pain and healthy controls. Participants marked positions of numbers on lines (number marking), before naming numbers on pre-marked lines (number naming). Finally, subjects bisected lines flanked with ‘2’ and ‘9’. Deviations from expected responses were determined for each experiment. RESULTS: Four hundred and ninety-four patients were audited; numeric scores in the ‘moderate’ and ‘severe’ pain categories were significantly higher in chronic compared with acute pain patients. In experiments (n=150), more than one-third of chronic pain patients compared with 1/10th of controls showed greater deviations from the expected in number marking and naming indicating impaired number sense. Line bisection experiments suggest prefrontal and parietal cortical dysfunction as cause of this impairment. CONCLUSIONS: Audit data suggest patients with chronic pain interpret numbers differently from acute pain sufferers. Support is gained by experiments indicating impaired number sense in one-third of chronic pain patients. These results cast doubts on the appropriateness of the use of visual analogue and numeric rating scales in chronic pain in clinics and research

Development, Validation, and Field-Testing of an Instrument for Clinical Assessment of HIV-Associated Neuropathy and Neuropathic Pain in Resource-Restricted and Large Population Study Settings

HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4-item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study–HIV-PINS). CHANT was alpha-tested in silico against the HIV-PINS dataset and then clinically validated and field-tested in HIV-positive cohorts in London, UK and Johannesburg, South Africa. The Utah Early Neuropathy Score (UENS) was used as the reference standard in both settings. In a second step, neuropathic pain in the presence of HIV-SN was assessed using the Douleur Neuropathique en 4 Questions (DN4)-interview and a body map. CHANT achieved high accuracy on alpha-testing with sensitivity and specificity of 82% and 90%, respectively. In 30 patients in London, CHANT diagnosed 43.3% (13/30) HIV-SN (66.7% with neuropathic pain); sensitivity = 100%, specificity = 85%, and likelihood ratio = 6.7 versus UENS, internal consistency = 0.88 (Cronbach alpha), average item-total correlation = 0.73 (Spearman’s Rho), and inter-tester concordance > 0.93 (Spearman’s Rho). In 50 patients in Johannesburg, CHANT diagnosed 66% (33/50) HIV-SN (78.8% neuropathic pain); sensitivity = 74.4%, specificity = 85.7%, and likelihood ratio = 5.29 versus UENS. A positive CHANT score markedly increased of pre- to post-test clinical certainty of HIV-SN from 43% to 83% in London, and from 66% to 92% in Johannesburg. In conclusion, a combination of four easily and quickly assessed clinical items can be used to accurately diagnose HIV-SN. DN4-interview used in the context of bilateral feet pain can be used to identify those with neuropathic pain

General principles of preclinical study design.

Preclinical studies using animals to study the potential of a therapeutic drug or strategy are important steps before translation to clinical trials. However, evidence has shown that poor quality in the design and conduct of these studies has not only impeded clinical translation but also led to significant waste of valuable research resources. It is clear that experimental biases are related to the poor quality seen with preclinical studies. In this chapter, we will focus on hypothesis testing type of preclinical studies and explain general concepts and principles in relation to the design of in vivo experiments, provide definitions of experimental biases and how to avoid them, and discuss major sources contributing to experimental biases and how to mitigate these sources. We will also explore the differences between confirmatory and exploratory studies, and discuss available guidelines on preclinical studies and how to use them. This chapter, together with relevant information in other chapters in the handbook, provides a powerful tool to enhance scientific rigour for preclinical studies without restricting creativity

Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated

Differences in Somatosensory Function Related to Hand Dominance: Results of a Quantitative Sensory Testing Study in Healthy Volunteers

Donna L Kennedy,1,2 Imogen Pateman,1 Andrew SC Rice,3 Caroline M Alexander1,2 1Therapy Department, Imperial College Healthcare NHS Trust, London, UK; 2Human Performance Group, Department of Surgery and Cancer, Imperial College London, London, UK; 3Pain Research Group, Department of Surgery and Cancer, Faculty Medicine, Imperial College London, London, UKCorrespondence: Donna L Kennedy, Therapy Department, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, United Kingdom, Email [email protected]: Quantitative sensory testing commonly utilizes the unaffected, contralateral side as a control to detect somatosensory dysfunction. There is scant evidence that somatosensory function for the volar dominant and non-dominant hands is equivalent, therefore intra-patient comparisons are unwarranted. This study aimed to identify dominance-related differences in palmar hand somatosensation, thereby determining if the unaffected contralateral hand is a valid comparator in clinical populations.Participants and Methods: With ethical approval (IREC_13_1_10) and informed consent, 110 healthy adult volunteers’ participated in this clinical measurement study. Somatosensory function was assessed with the German Research Network on Neuropathic Pain (DFNS) quantitative sensory testing (QST) protocol. Half of the participants were tested on the dominant hand. Thirteen parameters of thermal and mechanical detection and pain threshold were evaluated at both the dorsal and volar hand (distal middle finger). Tests were performed in the same order and instructions were read from a standardized script. Results for dorsal hand tests were compared to DFNS normative data to confirm participants met study inclusion criteria. Between-group differences for age and sex were investigated with the independent samples t-test and Chi-square test of independence, respectively. Group differences for dominant and non-dominant hands for all 13 continuous QST parameters were investigated with the Mann–Whitney U-test.Results: Data for 106 participants were included in statistical analysis. Fifty percent of participants were tested on the dominant hand [n=53]; there were no differences for age or sex between groups (dominant or non-dominant hand test group). The dominant volar hand was significantly more sensitive to vibration detection threshold than the non-dominant hand (P=0.001). There were no significant differences related to dominance for other DFNS QST measures.Conclusion: For quantitative sensory testing with the DFNS protocol in healthy cohorts, the contralateral, unaffected hand is a valid control, with the exception of vibration detection threshold.Keywords: thermoreception, mechanoreception, vibration, pain, evaluatio

Flight Lieutenant Peach’s observations on Burning Feet Syndrome in Far Eastern Prisoners of War 1942-45

This historical review analyses ‘Burning Feet Syndr ome’, a condition suffered by Far Eastern Prisoners of War in the Second World War. Case reco rds from RAF doctor Nowell Peach, written at the time, are retrospectively assessed a gainst modern diagnostic criteria to determine if the syndrome can be retrospectively cl assed as neuropathic pain

Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy

Non-freezing cold injury (NFCI) develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intra-epidermal nerve fibre assessment. Of the 42 study participants, all had experienced NFCI whilst serving in the United Kingdom armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localised to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases large fibre nerve conduction studies were normal. The intra-epidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) grading for neuropathic pain 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients

Mechanical detection and pain thresholds: comparability of devices using stepped and ramped stimuli

Quantitative sensory testing is used to assess somatosensory function in humans. The protocol of the German Research Network on Neuropathic Pain (DFNS) provides comprehensive normative values using defined tools; however, some of these may not be feasible in low-resource settings. Objectives: To compare the standard DFNS devices for assessment of mechanosensory function to a low resource tool, the Sorri-Bauru-monofilaments. Methods: Mechanical detection thresholds (MDT), pain thresholds (MPT), and suprathreshold pinprick ratings (pain sensitivity: MPS) were measured over cheek, hand dorsum, and fingertip in 13 healthy subjects (7 female, aged 21-44 years). Mechanical detection threshold was assessed with DFNS standard glass monofilaments (0.25-512 mN, 0.5 mm tip) and nylon monofilaments (Sorri-Bauru; 0.5-3000 mN). MPT was assessed with DFNS standard cylindrical probes (8-512 mN, 0.25 mm tip), Sorri-Bauru monofilaments, and with ramped stimuli using an electronic von Frey aesthesiometer (10 mN/s or 100 mN/s, 0.20 mm tip). MPS was measured in response to stepped and ramped pinpricks (128 and 256 mN). Results: Mechanical detection thresholds were the same for DFNS and Sorri-Bauru monofilaments. For MPT, Sorri-Bauru filaments yielded lower values than PinPricks over face but not hand. Pain thresholds were higher at all test sites for ramped than stepped pinpricks (P < 0.01). Suprathreshold ratings were lower for ramped than stepped pinpricks (P < 0.05). Conclusion: Sorri-Bauru filaments are acceptable substitutes for DFNS standards in estimating tactile sensitivity, but are not consistent with standard probes for pinprick sensitivity because of their nonstandardized tips. Ramped stimuli overestimated MPT and underestimated MPS due to reaction time artefacts and therefore need their own normative values