Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state

Abstract

Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon is poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared to Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared to SD counterparts. Equivalent plasma morphine levels in the two rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal grey (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of vlPAG, namely the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.

Simultaneous Administration of Hyperbaric Oxygen Therapy and Antioxidant Supplementation with Filipendula ulmaria Extract in the Treatment of Thermal Skin Injuries Alters Nociceptive Signalling and Wound Healing

“…The alterations in opioid/nociceptive receptors may be included in the mechanisms underlying different behavioural alterations that occur concomitantly with injuries. Thus, the changes in opioid/nociceptive receptors have been shown to influence various behavioural aspects, including anxiety and depressive state-level alterations [ 49 , 52 , 53 ] and cognitive function impairment [ 54 ], as well as alterations in nociception [ 53 ]. The beneficial role of melatonin system alterations in both peripheral and spinal cord levels was also previously reported using thermal nociceptive hypersensitivity in neuropathic rats [ 55 ].…”

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

“… 49 In our study, the highest dose of systemic morphine studied produced comparable inhibitory effects on MIA-induced pain behaviour in both strains of rats, thus reduced efficacy of opioid signalling, rather than a loss of receptors in WKY rats, is likely to explain these differences in the effects of morphine. Plasma levels of morphine after systemic administration have been shown to be equivalent in WKY and SD rats, 23 and therefore, metabolism of exogenous opioids is an unlikely confounder. Reduced efficacy of morphine in WKY rats has been reported in both acute pain tests and the formalin model, 23 and here, we report blunted opioid analgesia in a clinically relevant model of chronic OA pain in WKY rats.…”

“…Plasma levels of morphine after systemic administration have been shown to be equivalent in WKY and SD rats, 23 and therefore, metabolism of exogenous opioids is an unlikely confounder. Reduced efficacy of morphine in WKY rats has been reported in both acute pain tests and the formalin model, 23 and here, we report blunted opioid analgesia in a clinically relevant model of chronic OA pain in WKY rats. Our data are consistent with the clinical evidence that anxiety in people with joint pain is associated with the greater 8 or more prolonged 41 use of prescription opioids.…”

Role of 5-HT1A-mediated upregulation of brain indoleamine 2,3 dioxygenase 1 in the reduced antidepressant and antihyperalgesic effects of fluoxetine during maintenance treatment

“…To examine whether the fluoxetine effects on comorbid pain and depression would be diminished during maintenance treatment, we used three depression-pain comorbidity models (genetic predisposition, chronic social stress, CFA-induced hindpaw monoarthritis). ( 1) Wistar-Kyoto (WKY) rats, a genetic model of depression and hyperalgesia (Pare, 1994), (Millard et al, 2020;Ferdousi et al, 2021), had depression-like behavior shown as increased baseline immobility time in forced swimming test (FST) (Figure 1A, unpaired t-test, n = 8, t = 7.743, df = 14, p < 0.0001) and hyperalgesia-like behavior shown as decreased baseline paw withdrawal latency (PWL) in thermal hyperalgesia test (TH) (Figure 1B, unpaired t-test, n = 8, t = 6.420, df = 14, p < 0.0001) as compared with Wistar rats. WKY rats were genetically resistant to the fluoxetine (10 mg/kg, i. p.) effect on depression (Figure 1C, RM 2-way ANOVA, n = 8/group, F (1,14) = 0.399, p = 0.538) and hyperalgesia (Figure 1D, RM 2-way ANOVA, n = 8/group, F (1,14) = 0.0573, p = 0.814) as demonstrated following 14 consecutive days of treatment.…”