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Pain expertise. Click here to book in your research studies.

Discovery of novel analgesic and anti-inflammatory drugs leverages various rodent and non-rodent models of pain. At InterVivo (IVS) and Transpharmation (TPH), we offer a wide range of pain models including post-surgical, inflammatory, burn and neuropathic. Benchmarking novel drugs against approved drugs offers a key path to identify novel drugs of interest, but further development is often plagued by clinical failures. We are often asked if spontaneous pain assays could improve the translational ability of preclinical results to the clinic. In addition to standardised evoked pain measures, we have investigated several approaches to assess spontaneous pain, biomarker changes and potentially quality of life in our pain models.
Assessing Pain in Rodents

Together, IVS and TPH offer a comprehensive range of validated pain assays both in the mouse and rat which are summarised below.
Neuropathic pain
• Spared nerve injury (SNI; Decostered & Woolf, 2000) [rat and mouse]
• Chronic constriction injury (CCI; Bennett & Xie, 1988) [rat and mouse]
• STZ-induced neuropathic pain (diabetic neuropathy) [rat]
• Chemotherapy-induced neuropathic pain (oxaliplatin, paclitaxel) [rat and
mouse]
Inflammatory pain
• FCA (intra-plantar; Pearson, 1956) [rat and mouse]
• Carrageenan (intra-plantar) [rat and mouse]
• Monosodium iodoacetate (MIA)-induced OA (synovial knee space) [rat and
mouse]
Acute/Post-operative pain
• Incisional pain (Brennan et al, 1995) [rat and mouse]
 Other chemically- or thermally-induced pain models
• Formalin (Hunskaar & Hole, 1987) [rat and mouse]
• Capsaicin (intra-dermal or intra-plantar) [rat and mouse]
• UV burn model of local cutaneous hyperalgesia and inflammation [rat]
• Compound 48/80-induced “itch” model (Sugimoto et al, 1998) [mouse]
• Acute pain, e.g. hot/cold plate, tail flick [rat and mouse]
While the primary mode of efficacy testing is through traditional response measures to evoked stimuli, e.g tactile (Von Frey), thermal, a variety of other measures have been developed and applied to certain tests based on their applicability. These include weight bearing, paw volume,
laser doppler (blood flow) and molecular biomarkers notably cytokines (see below).
Figure 1. Male, SD rats received a single intra-plantar injection of FCA (100uL; 1mg/ml) and paw tissue collected 5 and 30 days later. A significant increase in the cytokines IL-1β and IL-6, but not TNFα was measured 5 days post injection. By 30 days post FCA injection IL-1β and IL-6 levels had returned to baseline.
Additional methods of assessing pain in preclinical rodent models has focussed on alternative non-evoked behaviours ranging from burrowing, gait analysis to cognitive changes. As evidence of our commitment to model development, follow the links to review our publications relating to the application of burrowing and gait (https://pubmed.ncbi.nlm.nih.gov/23747575/) and cognitive measures of attention and motivation (https://pubmed.ncbi.nlm.nih.gov/25746510/) applied to the rat spared nerve injury model of neuropathic pain first described by Decostered and Woolf (2000).
More recently we have been using electroencephalography (EEG) techniques to identify changes in brain oscillatory activity as well as changes in sleep architecture to the rat oxaliplatin pain model. A potential key benefit of using EEG in preclinical neuropathic pain research is its translatability to humans. Clinical EEG has not only been used to measure neuropathic pain but also to classify and even predict patients that will develop this condition. Whilst the main benefit of preclinical EEG recordings is the potential for improved translation of pharmacological interventions, EEG has also been part of direct non-pharmacological, non- invasive treatments for neuropathic pain. Recent advances in using EEG to measure, classify or even help managing neuropathic pain highlights the translatability and versatility of EEG as a method of identifying new and better pain treatments. Changes in EEG signal have the future potential to become objective measures of pain in both preclinical and clinical settings.

Together, this highlights the commitment of InterVivo Solutions and Transpharmation to develop refined pain models with the potential to provide better translatability and client value. Follow this link to our recent translational review of Preclinical Neuropathic Pain Assessment (https://www.frontiersin.org/articles/10.3389/fphar.2020.614990/full).
Author: Guy Higgins, Global Chief Scientific Officer 
The Translational Value of Naturally Occurring Pain in Dogs

Unlike rodents, which like many predatory species tend to mask behavioural evidence of pain, dogs naturally develop pain and show overt signs of pain that can be measured using various non-evoked pain assays. Osteoarthritis, for example, impacts approximately 20% of the pet population and several non-steroidal anti-inflammatory drugs are approved in humans and dogs (e.g. meloxicam).  Approximately 40% of our aged dog colony shows both radiographic and behavioural evidence of osteoarthritis. To assess pain, we have developed a laboratory adaption of the canine brief pain inventory (CBPI) which assesses pain and motivation during normal activities of daily living, such as walking, trotting, climbing stairs and stepping over obstacles. We have shown that meloxicam is able to reduce pain and improve function, or motivation, when compared to control (Figure 2).
Figure 2: N=6 dogs with naturally occurring OA per group were evaluated on the modified CBPI following either placebo or 0.2 mg/kg PO meloxicam. Pain declined and function (motivation) improved compared to the first day of testing with repeated administration over five days.
Additional non-evoked pain measures include sleep-wake activity measures, obstacle maze performance and gait assessed using a force mat. We also have the ability to examine plasma and synovial fluid biomarkers in dogs, which can be used to evaluate the effects of novel anti- inflammatory drugs. Our initial research shows that IL-6 and IL-8 levels are increased in osteoarthritic dogs compared to aged-matched normal (Figure 3).
Figure 3: IL-6 (left panel) and IL-8 (right panel) levels in plasma samples from n=15 non-osteoarthritic dogs and n=12 osteoarthritic dogs were quantified using a commercially available canine multiplex cytokine kit and analyzed by the MESO QuickPlex SQ.
To support therapeutic development in our naturally occurring OA colony of dogs, we have also developed a self-limiting inflammation test using sodium urate injection into the stifle. Again, meloxicam is able to reverse both oedema and pain more rapidly than the return to baseline seen in seven days (Figure 4).
Figure 4: N=8 dogs per group were evaluated for both pain (left panel) measured by the modified CBPI and oedema (right panel), measured by joint circumference following treatment with meloxicam or negative control in response to sodium urate injection. Pain was significantly reduced by meloxicam compared placebo 4, 8 and 24 hours following administration of treatment. Similarly, meloxicam significantly reduced urate-induced oedema compared to negative control. 
The use of dogs provides not only an opportunity to increase the translational value of pain research, but also establishes a potential secondary market in the companion animal health market, and we would welcome the opportunity to explain how we can help with both these opportunities.
Author: Christina de Rivera, Chief Scientific Officer, Companion Animal Department 

Learn more at the International Association for the Study of Pain meeting in Toronto!

Visit us at the IASP 2022 World Congress on Pain in Toronto, September 19th-23rd, booth number 1406, to learn more about our capabilities in rodent and canine models for evaluating novel therapeutics for pain, or to discuss your needs.
See our pain services. Click here.
Transpharmation recently merged with InterVivo Solutions, forming the largest boutique Neuroscience-specialised small and large animal CRO, with a delivery spanning North America, Asia, UK and Europe, and increased capacity and opportunities for collaboration.

Transpharmation is a global CRO, with an extensive number of services and decades of scientific expertise. We feel passionately about what we do and the difference it makes.

For all preclinical study enquiries or to find out how we can help develop your research further, please contact me at any time: mark.duxonceo@transpharmation.co.uk
Be sure to follow Transpharmation on LinkedIn and keep an eye on our website for up-to-date information.
Wherever you are based around the world, we can work with you.
I look forward to speaking to you soon. Thank you.

Dr.Mark Duxon
CEO of Transpharmation and InterVivo Solutions

Preclinical services:

Psychedelics / PK / PD Bioanalysis / Pain / Neuropathic pain / Alzheimer’s Disease / Depression/anxiety / Schizophrenia / Inflammatory pain / Cognitive disorders / Mismatch Negativity (MMN) / Molecular Biomarkers / Sleep/wake / QEEG / ASSR / Neuroinflammation / HTS in Zebrafish / PBMCs...and more.
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Copyright © Transpharmation PK and safety studies newsletter Sept 21st 2022

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