Association between sensitisation and pain-related behaviours in an experimental canine model of osteoarthritis

Abstract

Evaluation of nociceptive sensitisation in canine osteoarthritis studies has been poorly reported, or even related to other clinical symptoms. In 16 dogs, peak vertical force (PVF), subjective pain assessment using 3 scales, sympathetic stress response with electrodermal activity (EDA) measurement, and behavioural changes with video analysis and telemetered motor activity were quantified at baseline (D-7), and 28 and 56 days post transection of the cranial cruciate ligament. As markers of central sensitisation, selected spinal cord biomarkers (substance P and transthyretin) were quantified at D56. Electrical withdrawal thresholds on the stifle and the tail were measured as indicative of peripheral and central quantitative sensory testing (QST) sensitisation, respectively. The effects of vehicle administration (n=8) were compared with tiludronate (2mg/kg subcutaneously, q2 week, starting at D0) administration. Generalized estimated equations tested the association between the behavioural and physiological methods and QST sensitisation, and therefore the sensitivity of the methods for detecting treatment efficacy. Compared to tiludronate, at D56, vehicle-treated dogs had increased spinal substance P (P=0.01), concomitant decreased transthyretin (P=0.02), and (compared to baseline) demonstrated peripheral and central QST sensitisation, which was not present for tiludronate. Only PVF, the spontaneous behaviour "walking with full weight-bearing," and EDA were associated with occurrence of QST sensitisation and indicated significant tiludronate analgesic efficacy after inclusion of central QST sensitisation as a predictor variable in the statistical model. This study establishes the strong interest to implement QST as a predictor of canine osteoarthritis pain symptoms explained by pain sensitisation.

Spontaneous dog osteoarthritis — a One Medicine vision

“…Quantitative sensory testing (QST), a method of quantifying pain, has been used to demonstrate central sensitization in human OA 182,183 , experimental dog OA 184 and spontaneous dog OA 185 . QST has also been used to demonstrate the efficacy of dog total hip replacements for reversing hyperalgesia 186 , as occurs in humans 187 .…”

The effect of intra-articular botulinum toxin A on substance P, prostaglandin E2, and tumor necrosis factor alpha in the canine osteoarthritic joint

“…Increased level of SP in synovial fluid (SF) has been related both to OA and to joint pain in horses [6, 7], and the upregulation of SP-positive nerve fibers in the joint is associated with painful OA in human patients [8]. Nerve fibers containing SP have been found in various joint structures of dogs [9–11]; and recently, the concentration of SP in the spinal cord has been associated with central sensitization and pain in dogs with experimental OA [12]. However, to our knowledge the SF SP concentration and its association with osteoarthritic pain have not been studied in this species.…”

Sensitivity of functional targeted neuropeptide evaluation in testing pregabalin analgesic efficacy in a rat model of osteoarthritis pain

“…As of today, pain perception and its intensity in animals is mainly a subjective evaluation. Therefore, a concurrent validation approach, with functional targeted neuropeptide evaluation as a reference, has demonstrated huge interest in determining test article analgesic efficacy in various pain conditions, and in various animal species, such as cow and dog …”

“…Therefore, a concurrent validation approach, with functional targeted neuropeptide evaluation as a reference, has demonstrated huge interest in determining test article analgesic efficacy in various pain conditions, and in various animal species, such as cow and dog. 13,14 Pregabalin (PGB) ((S)-3-(aminomethyl)-5-methylhexanoic acid) is an anticonvulsant and an analgesic drug related to gabapentin, binding to the alpha 2 -delta (α 2 -δ) auxiliary subunit of voltage-dependent calcium channels and consequently, decreasing central sensitization in the central nervous system by diminishing the intracellular influx of calcium into the presynaptic neuron. 15,16 Neurotransmitters that are sensitive to PGB or gabapentin includes glutamate from rat neocortex, entorhinal cortex, or hippocampus, [17][18][19] spinal glutamate, 20 SP and CGRP from spinal cord dorsal horn 21 and norepinephrine from neocortex.…”