Further evidence validating adjuvant arthritis as an experimental model of chronic pain in the rat

doi:10.1016/0024-3205(82)90402-7

Life Sciences

Volume 31, Issue 1, 5 July 1982, Pages 67-75

https://doi.org/10.1016/0024-3205(82)90402-7 Get rights and content

Abstract

The experiments described here were aimed at further validating adjuvant arthritis as an animal model of chronic pain. It was found that the relative oral intake of a 0.008 mg/ml solution of fentanyl was higher in arthritic than in normal control rats; this difference was predicted by the notion that the analgesic effect of a substance may reinforce its intake in animals exposed to pain, more so than in normal pain-free animals. It was also found that body weight decreases and that vocalizations of aggregated rats increase as a result of the challenge; these effects suggest that the vegetative signs and the behavioral irritability which are characteristic of chronic pain in humans, also occur in arthritic animals. The pain which thus seems to be associated with adjuvant arthritis was estimated to have its onset on days 10–11, to peak on days 18–21, and to terminate on days 35–40 after inoculation with $Mycobacterium butyricum$ .

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One study found that arthritic rats self-administered IV morphine at a lower rate than control animals, an effect that was reversed by indomethacin, suggesting that inflammatory pain reduces the reinforcing effects of opioids (Lyness et al., 1989). Conversely, oral intake of fentanyl was shown to increase with the development of CFA-induced arthritis in rats, and intake mirrored the arthritic process (Colpaert et al, 1982, 2001). Additionally, CFA-induced arthritis attenuated low dose heroin self-administration under both FR and PR schedules of reinforcement in rats, whereas high-dose heroin self-administration approximately doubled under the FR schedule but did not change under the PR schedule (Hipólito et al., 2015).
Pain is a complex experience with far-reaching organismal influences ranging from biological factors to those that are psychological and social. Such influences can serve as pain-related risk factors that represent susceptibilities to opioid use disorder. This review evaluates various pain-related risk factors to form a consensus on those that facilitate opioid abuse. Epidemiological findings represent a high degree of co-occurrence between chronic pain and opioid use disorder that is, in part, driven by an increase in the availability of opioid analgesics and the diversion of their use in a non-medical context. Brain imaging studies in individuals with chronic pain that use/abuse opioids suggest abuse-related mechanisms that are rooted within mesocorticolimbic processing. Preclinical studies suggest that pain states have a limited impact on increasing the rewarding effects of opioids. Indeed, many findings indicate a reduction in the rewarding and reinforcing effects of opioids during pain states. An increase in opioid use may be facilitated by an increase in the availability of opioids and a decrease in access to non-opioid reinforcers that require mobility or social interaction. Moreover, chronic pain and substance abuse conditions are known to impair cognitive function, resulting in deficits in attention and decision making that may promote opioid abuse. A better understanding of pain-related risk factors can improve our knowledge in the development of OUD in persons with pain conditions and can help identify appropriate treatment strategies.
This article is part of the special issue on ‘Vulnerabilities to Substance Abuse.’.
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Across centuries and civilizations opioids have been used to relieve pain. In our modern societies, opioid-based analgesics remain one of the most efficient treatments for acute pain. However, the long-term use of opioids can lead to the development of analgesic tolerance, opioid-induced hyperalgesia, opioid use disorders, and overdose, which can ultimately produce respiratory depressant effects with fatal consequences. In addition to the nociceptive sensory component of pain, negative affective states arising from persistent pain represent a risk factor for developing an opioid use disorder. Several studies have indicated that the increase in prescribed opioid analgesics since the 1990s represents the root of our current opioid epidemic. In this review, we will present our current knowledge on the endogenous opioid system within the pain neuroaxis and the plastic changes occurring in this system that may underlie the occurrence of pain-induced negative affect leading to misuse and abuse of opioid medications. Dissecting the allostatic neuronal changes occurring during pain is the most promising avenue to uncover novel targets for the development of safer pain medications. We will discuss this along with current and potential approaches to treat pain-induced negative affective states that lead to drug misuse. Moreover, this chapter will provide a discussion on potential avenues to reduce the abuse potential of new analgesic drugs and highlight a basis for future research and drug development based on recent advances in this field.
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Many individuals continue to use opiates due to concerns about pain (Barth et al., 2013). Previous work supported the idea that the presence of pain was protective against the development of an addiction phenotype (Colpaert et al., 1982, 2001; Lyness et al., 1989; Ozaki et al., 2004), however there is growing evidence that this is not the case (Ewan and Martin, 2013; Hou et al., 2015; Zhang et al., 2014) and epidemiological studies find evidence of misuse and addiction among individuals with chronic pain (Vowles et al., 2015). This study provides possible targets for treating the pain that is associated with chronic opiate usage.
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Fourteen patients with non-alcoholic chronic pancreatitis that have been taking prescription opiates for 6 or more months and 14 gender matched, non-opiate using controls were enrolled. Functional neuroimaging data was acquired while participants received blocks of thermal stimulation to their wrist (individually-tailored to their pain threshold).
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The findings suggest that in chronic pancreatitis patients, a dose of opiates that normalizes their behavioral response to acute pain is associated with an amplified neural response to acute pain. Further longitudinal studies are needed to determine if this neural sensitization hastens a behavioral tolerance to opiates or the development of an opioid use disorder.
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Intracranial self-stimulation (ICSS) is one procedure that can be used for preclinical abuse potential assessment. In ICSS procedures, subjects with microelectrodes implanted into a brain-reward region are trained to press an operant response lever for pulses of electrical brain stimulation, and drugs are evaluated for their effectiveness to increase or “facilitate” ICSS responding (an abuse-related effect) or to depress ICSS responding (an abuse-limiting effect). ICSS has been used for decades to evaluate determinants of opioid abuse potential, and this article reviews pharmacological and biological determinants of opioid abuse potential as revealed by ICSS studies in rodents. One of the most important observations from ICSS studies is that abused mu opioid receptor (MOR) agonists like morphine often fail to produce abuse-related ICSS facilitation in opioid-naïve subjects, but several days of repeated opioid exposure is sufficient for opioid-induced facilitation to emerge. Future studies with ICSS could help (a) to clarify mechanisms that increase MOR agonist abuse potential during early opioid exposure or during chronic exposure leading to dependence, (b) to evaluate novel opioids either developed as candidate analgesics with reduced abuse potential or identified as designer opioids being synthesized and distributed for illicit use, and (c) to test candidate pharmacotherapies for treatment of opioid abuse in non-dependent and dependent subjects.
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Rheumatoid arthritis is a chronic inflammatory joint disease characterized by synovial proliferation and tissue destruction. Pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play a key role in the disease process and elevate energy expenditure, which further increases the joint pain and stiffness. The present study was undertaken to explore the anti-arthritic potential of fenugreek mucilage in adjuvant induced arthritic rats. In the present study, paw volume was measured on the 7^th, 14^th and 21^st day. Finally, animals were anaesthetized; blood samples and tissues were collected for the assay of inflammatory enzymes like cyclooxygenase, lipoxygenase; evaluated the level of cytokines like IL-6, TNF-α, arthritic index and rheumatoid factor. Fenugreek mucilage exhibited maximum percentage of edema inhibition at a dose of 75 mg/kg on 21st day of adjuvant arthritis. The effect was higher than that of standard drug, indomethacin. The activities of inflammatory enzymes and concentration of mediators were decreased on treatment with fenugreek mucilage. Cytology of synovial fluid showed mild inflammation with normal synoviocytes (mesothelial cells) tried to bring back to normal characteristics on supplementation with fenugreek mucilage. Based on the observations, it can be suggested that fenugreek mucilage possesses promising anti-arthritic property and it can be used as a therapeutic agent for arthritis.
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The effects induced by thiamine and riboflavin, isolated or in association with corticosteroids, in models of chronic inflammation are not known. Thus, we evaluated the effect induced by these B vitamins, isolated or in association with dexamethasone, on the mechanical allodynia, paw edema and cytokine production induced by complete Freund’s adjuvant (CFA) in rats.
Chronic inflammation was induced by two injections of CFA. Nociceptive threshold, paw volume and body temperature were evaluated for 21 days. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) contents were determined in paw tissue. Riboflavin (125, 250 or 500 mg/kg) or thiamine (150, 300 or 600 mg/kg) were administered per os (po), twice daily. Dexamethasone (0.5 mg/kg day, po) was administered every three days.
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Riboflavin and thiamine exacerbate the anti-inflammatory activity of dexamethasone and reduce production of TNF-α and IL-6.

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Further evidence validating adjuvant arthritis as an experimental model of chronic pain in the rat

Abstract

Pain

Life Sci.

Life Sci.

Pain

Eur. J. Pharmac.

Pain

Archs. int. Pharmacodyn. Thér.

Meth. Archs. exp. Path.

Arzneimittel-Forsch.