Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia

Abstract

Title (20 words): Anxiety enhances pain in a model of osteoarthritis and is 1 associated with altered endogenous opioid function and reduced opioid 2 analgesia 3 4 Abstract 238 words, introduction 629 words, discussion 1138 words 26 27 28 29 30 31 32 Abstract (239) 34Chronic pain states such as osteoarthritis (OA) are often associated with negative 35 affect, including anxiety and depression. This is, in turn, associated with greater 36 opioid analgesic use, potentially contributing to current and future opioid crises. We 37 utilise an animal model to investigate the neurobiological mechanisms underlying 38 increased opioid use associated with high anxiety and chronic pain. 39 Combining a genetic model of negative affect, the Wistar Kyoto (WKY) rat, and intra-40 articular injection of monosodium iodoacetate (MIA; 1mg), our model of high anxiety 41 and augmented OA-like pain behaviour mirrors the clinical problem. Effects of 42 morphine (0.5-6mg.kg -1 ) on pain behaviour and spinal nociceptive neuronal activity 43 were determined in WKY rats, and normo-anxiety Wistar rats, 3 weeks after MIA 44 injection. WKY rats developed augmented OA-like pain, and had blunted inhibitory 45 responses to morphine, when compared to Wistar rats. Potential alterations in 46 endogenous opioid function were probed via systemic blockade of opioid receptors 47 Significance Statement (116) 56 Chronic pain affects large numbers of people, and pain management often relies on 57 poorly effective opioid analgesics, the iatrogenic effects of which are increasingly 58 recognised. The endogenous opioid system -the target for exogenous opioid 59 analgesics -plays key roles in emotional affective states and pain control, but the 60 complex interplay between anxiety, chronic pain, and endogenous opioid system 61 function is challenging to study in people. Here, we have addressed this using a 62 clinically-relevant experimental model. Anxiety-like behaviour was associated with 63 increased chronic arthritis-like pain behaviour, altered opioid receptor function, and 64 reduced efficacy of opioid analgesics. We provide new evidence, which may explain 65 why chronic pain patients with comorbid high anxiety have higher opioid analgesic 66 use. 67Studies were in accordance with UK Home Office Animals (Scientific Procedures) 126 Act (1986) and ARRIVE guidelines (Kilkenny et al., 2012). A total of 183 male rats 127 were used for this study; Wistar n = 97 (Charles River, Margate, United Kingdom), & 128Wistar Kyoto n = 86 (WKY; Envigo, Bicester, United Kingdom). Males only were 129 used to reduce variability in the data, and to maintain consistency with previous 130 studies characterising this model. Wistar rats were used as the most genetically 131 similar control strain to WKY. Rats were group housed by strain in groups of 4 on a 132 12-hour light/dark cycle in a specific pathogen-free environment with ad libitum 133 access to standard rat chow and water. Treatments were randomly assigned to rats, 134 and experimenters were blinded to all treatment group...

No evidence for cognitive impairment in an experimental rat model of knee osteoarthritis and associated chronic pain

“…However, the sensitivity of the von Frey test to detect PWT reductions in Lister hooded rats is worth further consideration. Baseline PWTs were lower in Lister hooded rats (PWT log=0.8-0.9) than in SD rats (around PWT log=1.25 [32]), and, therefore this measure of pain behaviour is more sensitive to a floor effect in Lister hooded rats. In addition, Lister hooded rats are very inquisitive, which although beneficial for cognitive testing, makes von-Frey testing challenging.…”

“…Rats received a single intra-articular injection of either 3 mg/50 µL MIA (Sigma, UK) or 50 µL 0.9% saline (control group) through the infra-patellar ligament of the left knee, using a 30-gauge 8-mm hypodermic needle, under brief isoflurane anaesthesia (isoflurane 2.5 -3% in 1L/min O2) [32].…”