Electrophysiological characterisation of central sensitisation in canine spontaneous osteoarthritis

Abstract

In man, central sensitisation (CS) contributes to the pain of osteoarthritis (OA). Dogs with spontaneous OA may also exhibit CS. Electrophysiological reflex measurements are more objective than behavioural assessments and can be used to evaluate CS in preclinical and clinical studies. It was hypothesised that dogs suffering from OA would exhibit electrophysiological characteristics indicative of CS, associated with reduced diffuse noxious inhibitory controls (DNICs). One hundred and seventeen client-owned dogs were recruited to the study. Hind limb nociceptive withdrawal reflex thresholds, stimulus response, and temporal summation characteristics were recorded, during alfaxalone anaesthesia, from 46 OA dogs, 29 OA dogs receiving nonsteroidal anti-inflammatory drugs (OANSAIDs), and 27 breed- and weight-matched control dogs. Efficacy of DNIC was evaluated in 12 control and 11 of the OA dogs, by application of a mechanical conditioning stimulus to the contralateral forelimb. Nociceptive withdrawal reflex thresholds were higher in OA compared with control dogs (P = 0.02). Stimulus response characteristics demonstrated an augmented response in OANSAID dogs compared with OA (P < 0.001) and control (P < 0.001) dogs. Temporal summation demonstrated exaggerated C-fibre-mediated responses in both OA (P < 0.001) and OANSAID (P = 0.005) groups, compared with control animals. Conditioning stimulus application resulted in inhibition of test reflex responses in both OA and control animals (P < 0.001); control animals demonstrated greater inhibition compared with OA (P = 0.0499). These data provide evidence of neurophysiological changes consistent with CS in dogs with spontaneous OA and demonstrate that canine OA is associated with reduced DNIC.

Figure 1

Illustration of the number of animals recruited to each OA category, and attrition through different stages of the study.

Figure 2

During anaesthesia, a bulldog clip conditioning stimulus was applied for 20 seconds to the third digit of the left cranial limb, whilst electrical test stimuli were delivered to the right pelvic limb.

Figure 3

An example of temporal summation in the cranial tibial muscle (recorded from dog 71). The top channel is a stimulus marker channel, with a train of 8 1ms 10 mA stimuli delivered at a frequency of 1 Hz. The lower channel shows the early and late responses in the cranial tibial muscle. The time base is 0.2s/division.

Figure 4

An example of the electrical stimulus response curve recorded from the cranial tibial muscle in dog 98. The top channel is the stimulus marker channel, with each single line representing five 1 ms stimuli delivered at a frequency of 100 Hz. Eleven stimuli were delivered with a 60 second interval between them starting at 0.1 mA (baseline), 1 mA and increasing in 1 mA increments through to 10 mA. The middle channel shows the early responses in the cranial tibial muscle and the lower channel shows the rectified EMG response in the cranial tibial muscle. The time base is 0.2s/division

Figure 5

Illustration of the mean curves predicted by the general linear model for stimulus response of dogs within differing OA categories, assuming a weight of 25kg. Each data point for the control animals is based on 27 dogs, for the OA group it is based on 46 dogs and for the OANSAID group it is based on 29 dogs. For each animal the mean response to the two repetitions of the stimulus response curve was averaged prior to analysis. The Y axis represents the natural logarithm of the magnitude of the EMG response and the X axis shows the magnitude of the stimulating current.

Figure 6

Illustration of the mean curves predicted by the general linear model for the first occasion temporal summation late response for dogs within differing OA categories, assuming a weight of 25kg and age of 9 years. The Y axis represents the natural logarithm of the magnitude of the EMG response and the X axis shows stimulus number.

Figure 7

Effect of mechanical “conditioning” stimulation of the forepaw on electrically evoked “test” EMG reflexes in the cranial tibial muscle of the contralateral hindlimb. Clip was applied at time 0 for 20 secs. In the control group EMG responses to the test stimulus were reduced (greater % reduction in EMG) during clip application, indicating antinociception and a DNIC effect. When all time points were considered DNIC in the OA group (n = 11) was significantly less compared to control animals (n = 12) (P=0.016). Responses are medians, errors are 75^th percentiles.