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

Lillywhite, Amanda; Woodhams, Stephen G; Gonçalves, Sara; Watson, David J.; Li, Li; Burston, James J.; Gowler, Peter R W; Canals, Meritxell; Walsh, David A.; Hathway, Gareth J.; Chapman, Victoria

doi:10.1097/pr9.0000000000000956

Cited by 6 publications

(9 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Anxiety that is comorbid with chronic pain, in addition to being a clinical problem in itself, can enhance the overall experience of pain and alter the function of commonly-used analgesics, including opiates. 49 It is therefore crucial to study and treat pain in a more integrated manner, considering the entirety of its clinical presentation as well as the underlying peripheral and central mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala

et al. 2022

View full text Add to dashboard Cite

Chronic pain increases the risk of developing anxiety, with limbic areas being likely neurological substrates. Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels. Even less is known about the molecular mechanisms through which the brain encodes pain-related anxiety. This study examines how persistent inflammatory pain in a rat model would impact anxiety-like behaviors and corticosterone release, and whether these changes would be reflected in levels of global DNA methylation in brain areas involved in stress regulation. Complete Freund’s adjuvant (CFA) or saline was administered in the right hindpaw of adult male Wistar rats. Behavioral testing included the measurement of nociceptive thresholds (digital anesthesiometer), motor function (open field test), and anxiety-like behaviors (elevated plus maze and the dark-light box test). Corticosterone was measured via radioimmunoassay. Global DNA methylation (enzyme immunoassay) as well as DNMT3a levels (western blotting) were quantified in the amygdala, prefrontal cortex, and ventral hippocampus. CFA administration resulted in persistent reduction in nociceptive threshold in the absence of locomotor abnormalities. Increased anxiety-like behaviors were observed in the elevated plus maze and were accompanied by increased blood corticosterone levels 10 days after pain induction. Global DNA methylation was decreased in the amygdala, with no changes in DNMT3a abundance in any of the regions examined. Persistent inflammatory pain promotes anxiety -like behaviors, HPA axis activation, and epigenetic regulation through DNA methylation in the amygdala. These findings describe a molecular mechanism that links pain and stress in a well-characterized rodent model.

show abstract

Section: Discussionmentioning

confidence: 99%

Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala

et al. 2022

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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]. Health and welfare checks were performed immediately after anaesthetic recovery, daily for 5 days, and weekly thereafter.…”

Section: Methodsmentioning

confidence: 99%

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

Gonçalves

Hathway

Woodhams

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Although chronic pain states have been associated with impaired cognitive functions, including memory and cognitive flexibility, the cognitive effects of osteoarthritis (OA) pain remain to be clarified. The aim of this study was to measure cognitive function in the mono-iodoacetate (MIA) rat model of chronic OA-like knee pain. We used young adult male Lister hooded rats, which are well suited for cognitive testing. Rats received either a unilateral knee injection of MIA (3mg/50uL) or saline as control. Joint pain at rest was assessed for up to 12 weeks using weight-bearing asymmetry, and referred pain at a distal site using determination of hindpaw withdrawal thresholds (PWT). The watermaze delayed-matching-to-place (DMP) test of rapid place learning, novel object recognition (NOR) memory assay and an operant response-shift and -reversal task were used to measure memory and behavioural flexibility. Open field locomotor activity, startle response, and prepulse inhibition (PPI) were also measured for comparison. MIA-injected rats showed markedly reduced weight-bearing on the injured limb, as well as pronounced cartilage damage and synovitis, but interestingly no changes in PWT. Rearing was reduced, but otherwise locomotor activity was normal and no changes in startle and PPI were detected. MIA-injected rats had intact watermaze DMP performance, suggesting no substantial change in hippocampal function, and there were no changes in NOR memory or performance on the operant task of behavioural flexibility. Our finding that OA-like pain does not alter hippocampal function, unlike other chronic pain conditions, is consistent with human neuroimaging findings.

show abstract

“…Moreover, since HRW failed to alter the number of entries into the closed arms in the EPM or the number of squares crossed in the OF tests, its anxiolytic-like actions cannot be related to a motor impairment of the animal. Then, and considering that depression and anxiety are two important affective disorders and that both increase pain perception in animals with chronic pain [ 53 ], the anxiolytic and antidepressant effects of HRW, together with its pain-relieving actions, might permit treating inflammatory pain in a more effective and integrated form.…”

Section: Discussionmentioning

confidence: 99%

Treatment with Hydrogen-Rich Water Improves the Nociceptive and Anxio-Depressive-like Behaviors Associated with Chronic Inflammatory Pain in Mice

et al. 2022

View full text Add to dashboard Cite

Chronic inflammatory pain is manifested in many diseases. The potential use of molecular hydrogen (H2) as a new therapy for neurological disorders has been demonstrated. Recent studies prove its analgesic properties in animals with neuropathic pain, but the possible antinociceptive, antidepressant, and/or anxiolytic actions of H2 during persistent inflammatory pain have not been investigated. Therefore, using male mice with chronic inflammatory pain incited by the subplantar injection of complete Freud’s adjuvant (CFA), we assessed the actions of hydrogen-rich water (HRW) systemically administered on: (1) the nociceptive responses and affective disorders associated and (2) the oxidative (4-hydroxy-2-nonenal; 4-HNE), inflammatory (phosphorylated-NF-kB inhibitor alpha; p-IKBα), and apoptotic (Bcl-2-like protein 4; BAX) changes provoked by CFA in the paws and amygdala. The role of the antioxidant system in the analgesia induced by HRW systemically and locally administered was also determined. Our results revealed that the intraperitoneal administration of HRW, besides reducing inflammatory pain, also inhibited the depressive- and anxiolytic-like behaviors associated and the over expression of 4-HNE, p-IKBα, and BAX in paws and amygdala. The contribution of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 and NAD(P)H: quinone oxidoreductase 1 pathway in the analgesic activities of HRW, systemically or locally administered, was also shown. These data revealed the analgesic, antidepressant, and anxiolytic actions of HRW. The protective, anti-inflammatory, and antioxidant qualities of this treatment during inflammatory pain were also demonstrated. Therefore, this study proposes the usage of HRW as a potential therapy for chronic inflammatory pain and linked comorbidities.

show abstract

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

Abstract: Supplemental Digital Content is Available in the Text. Comorbid anxiety and osteoarthritis pain is associated with increased opioid intake. Our translational model identifies reduced opioid analgesia and endogenous opioid dysfunction as potential mechanisms.

Cited by 6 publications

References 64 publications

Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala

Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala

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

Treatment with Hydrogen-Rich Water Improves the Nociceptive and Anxio-Depressive-like Behaviors Associated with Chronic Inflammatory Pain in Mice

Contact Info

Product

Resources

About