Evaluation of pain experience in domestic fowl: associations between clinical symptoms biochemical markers and bird self-selection of analgesics

Lead Research Organisation: University of Edinburgh
Department Name: Royal (Dick) School of Veterinary Scienc

Abstract

Experience of pain causes unpleasant subjective feelings in humans and may do so in animals. To reduce animal suffering, we need to be able to assess the severity and duration of experienced pain. Current methods for pain assessment, based on animal behaviour and the effect of analgesics, are difficult to interpret: additional information is required to assess whether experiences which appear to be painful are actually experienced as such. In humans, Patient Controlled Analgesia for pain management is a widely accepted procedure as it is clearly motivated by subjective states of pain perception and is used as one of the 'gold standards' for the assessment of conscious experience of pain in man. A demonstration that animals could make complex decisions to manage their own pain would provide important new information on their pain experience, as decision-making itself takes place in higher centres in the brain, thought to be involved in the generation of conscious experience. Studies of animal decision-making have been applied only sporadically to the question of animal pain. We propose to develop methodology in this area and to investigate whether levels of the neurotransmitter dynorphin change due to pain experience. Interpretation of the results of the few studies of self-selection of analgesics in animals is problematic. We developed a pilot method for studying self-selection of analgesic drugs, presented in food, to broiler chickens but this needs development and refinement. Our pilot results suggested that lame birds ate more drug-treated feed than sound birds. However, interpretation of the pilot results in terms of pain experience was complicated by changes in the level of lameness of birds over the duration of the experiment, the voracious appetites of broilers, similar end-stage plasma analgesic levels in lame and sound birds, and uncertainties relating to effective dose. We propose to advance this area of science by studying two well-defined clinical problems in birds, lameness in broiler chickens and bone fractures in laying hens. Both of these conditions are widespread in commerical agriculture and, if they are accompanied by pain, they represent a significant animal welfare problem. We have selected two conditions because different conditions may cause different 'types' of pain, leading to varying patterns of analgesic selection. We also wish to compare the ability to self-select analgesia in immature (broilers) and mature (hens) domestic fowl. By conducting detailed longitudinal studies, we aim to obtain new information on changes in analgesic intake over time, the effects on behaviour and mobility of analgesic intake, and the relationship between changes in behaviour, clinical signs and levels of drug detected in the blood and tissues. We will develop our pilot protocol by carrying out initial studies and modifying the method used in the self-selection study. First, we will develop methods to track the changes in putative pain experience using several advanced methods available in other species and several novel methods, including advanced imaging techniques. Nerve tissue samples from birds from 'in pain' and 'pain free' groups thus identified will be assayed for dynorphin. Next, we will examine a range of modes of drug presentation, so that drug selection is not necessarily confounded with appetite. Then, we will assess how the level of the analgesic drugs used is associated with drug concentration in blood and in relevant tissues. Changes in clinical signs and in pain behaviour will be monitored in parallel. This will help us to know whether the blood levels of analgesics found in the final self-selection trials are likely to provide effective pain relief. Finally, using appropriate controls, we will assess whether domestic chickens reliably select analgesics when given the opportunity. This will enable us to assess the welfare impact of lameness and bone fractures in chickens.

Technical Summary

Interpretation of animal behavioural studies, in terms of pain experience, is problematic. A demonstration that animals can make complex decisions to manage their own pain would provide information on pain experience, as decision-making itself is a central brain process. We propose to develop methodology in this area and to investigate a putative measurable biochemical correlate of pain experience by measuring CNS dynorphin levels in birds. We developed a pilot method for studying self-selection of analgesic drugs to birds, which needs refinement. This method suggested that lame chickens preferentially selected analgesics in food. However, interpretation of these results in terms of pain experience was difficult as the lameness was of heterogeous origin and changed over time, and because pharmacokinetic and pharmacodynamic data for analgesics used was lacking. Here, we will study and compare two clearly-defined and widespread clinical conditions in domestic chickens, valgus leg disorders in broilers and keel bone fractures in laying hens. We will track changes in putative pain experience using a range of methods including latency to lie, changes in mechanical and thermal thresholds, thermal imaging, walking velocity and advanced imaging. We will thus identify homogenous 'pain' and 'pain free' groups, for which CNS dynorphin assay will be carried out. We will determine how the plasma and exudate analgesic levels change, using HPLC assay, and how different levels affect 'pain' related behaviour to aid interpretation of blood levels of analgesics. Finally, we will conduct self-selection experiments using the homogenous 'in pain' and 'pain free' groups identified, alongside appropriate controls, to determine whether these important clinical conditions lead birds to reliably and preferentially select either NSAID or opioid analgesics.

Publications

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Fallon M (2016) Randomized Double-Blind Trial of Pregabalin Versus Placebo in Conjunction With Palliative Radiotherapy for Cancer-Induced Bone Pain. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Fallon MT (2015) Cancer treatment-related neuropathic pain: proof of concept study with menthol--a TRPM8 agonist. in Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer

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Fleetwood-Walker S (2012) Assessment of animal pain and mechanism-based strategies for its reversal. in Veterinary journal (London, England : 1997)

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Gauff F (2013) Pain-associated changes in the dorsal root ganglia of laminitic horses in Journal of Equine Veterinary Science

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Menè P (2013) TRP channels as therapeutic targets in kidney disease and hypertension. in Current topics in medicinal chemistry

 
Description Keel-fractured hens (but not controls) displayed reduced mobility that was partially restored following opioid (butorphanol) treatment, together with conditioned place preference for butorphanol. This provides evidence that keel fractures are painful in hens, and that butorphanol administration can modulate this pain, improving mobility and inducing a positive affective state that is not seen in control birds.

Despite the broad heterogeneity of broiler lameness, diverse pain indices were successfully developed to provide evidence for factors (other than bodyweight) reducing walking ability within our test cohort. NSAID treatment increased standing time, walking velocity, and altered thermal threshold in lame broilers compared to non-lame controls. Modulation of our lameness biomarkers with analgesics provides evidence that lameness is associated with pain in broilers.

Biochemical markers of pain and inflammation (COX-2 and nociceptive TRP channels together with endogenous opioid and opioid receptors) were upregulated in keel-fractured layers and lame broilers.
Exploitation Route The outcomes will help to inform researchers in the field of animal pain, especially in avian species, where very little work has been achieved so far. Our findings also provide useful information in relation to animal welfare.
Sectors Agriculture, Food and Drink,Education,Healthcare,Pharmaceuticals and Medical Biotechnology,Other

 
Description National Health Scotland/Scottish Government Health Directive - Committee Member of Chronic Pain Research Steering Group (SPaRC).
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Dissemination of current research information on neurobiology of pain and analgesia to enhance the understanding and clinical practice of healthcare professionals.