Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

Cahill, Catherine M.; Walwyn, Wendy; Taylor, Austin L.; Pradhan, Amynah; Evans, Christopher J.

doi:10.1016/j.tips.2016.08.002

Cited by 98 publications

(80 citation statements)

References 127 publications

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“…In contrast to a previous study by ixcoatlZecuatl et al [17], our study showed that the PDE 5 inhibitor tadalafil decreased the analgesic effects of morphine while increasing the development of morphine tolerance [17]. Tolerance is characterized as a decrease in effect following prolonged drug administration giving rise to a loss of drug efficiency, which was sufficient to cause analgesia in the beginning [24]. The mechanisms behind the development of tolerance to the analgesic effects of opioids are unclear and more studies are needed.…”

Section: Discussioncontrasting

confidence: 89%

Effects of the phosphodiesterase type-5 inhibitor tadalafil on nociception, morphine analgesia and tolerance in rats

Taşkıran

Özdemir

Arslan

et al. 2018

j-ebr

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A B S T R A C TAim: Tadalafil is a potent, selective and reversible inhibitor of phosphodiesterase type 5 (PDE5) enzyme breakdowning cyclic guanosine monophosphate (cGMP). In this study, we aimed to investigate the effects of tadalafil on nociception, morphine analgesia and tolerance. Methods: In this study, 54 Wistar Albino (230-250 g) male rats were used. First of all, four different doses (2, 4, 8, 16 mg/kg) were used to determine the optimum effective dose of tadalafil on nociception. Optimum activity was found at 8 mg/kg and animals were divided into six groups: Saline (S), 8mg/kg tadalafil, 5mg/kg morphine (M), M+ tadalafil, morphine tolerance (MT) and MT+ tadalafil. Saline was given to the control group, tadalafil intraperitoneally and morphine subcutaneously administered at the indicated doses. To develop tolerance to morphine, 10mg/kg morphine was injected daily in the morning and evening for five days and tolerance was evaluated with single dose of morphine on sixth days. The resulting analgesic effect was measured with hot plate and tail flick analgesia tests and recorded at 30th, 60th, 90th and 120th minutes. Results: Tadalafil showed anti-nociceptive effect when given alone at different doses (p<0.05). However, tadalafil significantly decreased the analgesic effect of morphine (p<0.05). In addition, tadalafil significantly increased the tolerance to morphine (p<0.05). Conclusions: The phosphodiesterase type 5 inhibitor tadalafil have anti-nociceptive properties and it decreases analgesic effect of morphine, in addition improves tolerance development. These effects probably may occur via NO/cGMP pathway.

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Section: Discussioncontrasting

confidence: 89%

Effects of the phosphodiesterase type-5 inhibitor tadalafil on nociception, morphine analgesia and tolerance in rats

Taşkıran

Özdemir

Arslan

et al. 2018

j-ebr

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“…Furthermore the effect of morphine on the expression of genes enriched in D2-MSNs and on the D2-striatal connectome was offset by this DHA-enriched diet. These data show how this intervention offset allostatic adaptations known to be induced by chronic opioid exposure [38] without altering the proto-typical effects of activating the mu opioid receptor, the predominant target of morphine and other opioids.…”

Section: Discussionmentioning

confidence: 87%

“…As DHA supplementation altered specific behaviors induced by morphine, we next examined whether the supplemental DHA protocol used altered DHA content of the frontal cortex and striatum, regions known to be affected by prior opioid exposure, the frontal cortex and striatum [38]. …”

Section: Resultsmentioning

confidence: 99%

“…This dietary intervention also reduced the increase in anxiety, or state of negative affect, that could be a driving contributor to opioid-seeking behaviors and relapse [38]. We propose that, in addition to the current pharmaceutical compounds such as narcan or buprenorphine, that target the mu opioid receptor, DHA could be used to reduce the allostatic adaptations associated with chronic opioid exposure.…”

Section: Discussionmentioning

confidence: 99%

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Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids

et al. 2017

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Opiates, one of the oldest known drugs, are the benchmark for treating pain. Regular opioid exposure also induces euphoria making these compounds addictive and often misused, as shown by the current epidemic of opioid abuse and overdose mortalities. In addition to the effect of opioids on their cognate receptors and signaling cascades, these compounds also induce multiple adaptations at cellular and behavioral levels. As omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a ubiquitous role in behavioral and cellular processes, we proposed that supplemental n-3 PUFAs, enriched in docosahexanoic acid (DHA), could offset these adaptations following chronic opioid exposure. We used an 8 week regimen of n-3 PUFA supplementation followed by 8 days of morphine in the presence of this diet. We first assessed the effect of morphine in different behavioral measures and found that morphine increased anxiety and reduced wheel-running behavior. These effects were reduced by dietary n-3 PUFAs without affecting morphine-induced analgesia or hyperlocomotion, known effects of this opiate acting at mu opioid receptors. At the cellular level we found that morphine reduced striatal DHA content and that this was reversed by supplemental n-3 PUFAs. Chronic morphine also increased glutamatergic plasticity and the proportion of Grin2B-NMDARs in striatal projection neurons. This effect was similarly reversed by supplemental n-3 PUFAs. Gene analysis showed that supplemental PUFAs offset the effect of morphine on genes found in neurons of the dopamine receptor 2 (D2)-enriched indirect pathway but not of genes found in dopamine receptor 1(D1)-enriched direct-pathway neurons. Analysis of the D2 striatal connectome by a retrogradely transported pseudorabies virus showed that n-3 PUFA supplementation reversed the effect of chronic morphine on the innervation of D2 neurons by the dorsomedial prefontal and piriform cortices. Together these changes outline specific behavioral and cellular effects of morphine that can be reduced or reversed by dietary n-3 PUFAs.

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“…These data provide evidence that specific alterations in cortical and subcortical activity may promote pain avoidance in the context of negative affective states, and contributes to our understanding of opioid-induced pain avoidance and the cognitive/motivational dimension of pain. As such circuitry is heavily impacted by chronic or excessive opioid exposure, further interrogation of within- and between-circuit neuroadaptations is warranted to better understand the pathological intersection of pain and addiction (Shurman et al, 2010; Cahill et al, 2016). We propose the continued use of the mechanical conflict avoidance assay for the development of novel therapeutic strategies for pain (Borsook et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

et al. 2017

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Repeated use of opioids can lead to the development of analgesic tolerance and dependence. Additionally, chronic opioid exposure can cause a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may drive continued or escalated use of opioids to manage worsening pain symptoms. Opioid-induced hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the cognitive/motivational dimension of pain in a state of opioid dependence and withdrawal, we employed a recently developed non-reflex-based method for measuring pain avoidance-like behavior in animals (mechanical conflict avoidance test). Adult male Wistar rats were administered an escalating dose regimen of morphine (opioid-dependent group) or repeated saline (control group). Morphine-dependent rats exhibited significantly greater avoidance of noxious stimuli during withdrawal. We next investigated individual relationships between pain avoidance-like behavior and alterations in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoidance-like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain regions. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain.

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Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

Cited by 98 publications

References 127 publications

Effects of the phosphodiesterase type-5 inhibitor tadalafil on nociception, morphine analgesia and tolerance in rats

Effects of the phosphodiesterase type-5 inhibitor tadalafil on nociception, morphine analgesia and tolerance in rats

Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

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