Dissecting the relative contribution of central versus peripheral opioid analgesia: Are the analgesic and adverse effects of opioids inseparable?

Ringkamp, Matthias; Raja, Srinivasa N.

doi:10.1002/j.1532-2149.2012.00110.x

Cited by 4 publications

(5 citation statements)

References 20 publications

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“…However, they were resistant to the peripherally restricted antagonist naloxone methiodide. These findings support a preferential location of the antinociceptive effects of m opioids at central levels under our experimental conditions, and are consistent with previous studies (GreenwoodVan Meerveld and Standifer, 2008;Joshi et al, 2008;Thomas et al, 2008;Khalefa et al, 2012;Ringkamp and Raja, 2012). Among the opioids tested in WT mice (in the absence of s 1 blockade), only oxycodone had an antinociceptive effect that was partially reversible by naloxone methiodide, and this only occurs at the highest dose (8 mg/kg) of the antagonist.…”

Section: Modulation Of Peripheral M-opioidsupporting

confidence: 93%

“…Opioid-induced constipation is the most clinically relevant peripheral side effect of m-opioids (Benyamin et al, 2008;Al-Hasani and Bruchas, 2011;Ringkamp and Raja, 2012), and it is one of the main reasons for patients' voluntary withdrawal from opioid medication (Dhingra et al, 2013). We recently showed that although morphine-induced antinociception was potentiated in s 1 -KO mice, morphine-induced constipation remained unaltered (Sánchez-Fernández et al, 2013;Vidal-Torres et al, 2013).…”

Section: Introductionmentioning

confidence: 94%

“…Some of these effects are mediated through peripheral opioid receptors (e.g., constipation), whereas others are mediated at supraspinal sites (e.g., addiction, dependency, nausea, somnolence, respiratory depression) (Benyamin et al, 2008;Greenwood-Van Meerveld and Standifer, 2008;Al-Hasani and Bruchas, 2011;Ringkamp and Raja, 2012). Targeting peripheral opioid receptors has been proposed as a strategy to minimize opioid-induced side effects that are produced centrally (Sehgal et al, 2011;Ringkamp and Raja, 2012). However, since most of the analgesia from systemic opioids is produced normally at central sites, it seems difficult to dissociate antinociceptive effects from centrally induced side effects.…”

Section: Modulation Of Peripheral M-opioid Analgesia By S 1 Receptorsmentioning

confidence: 99%

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Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Sánchez-Fernández

Montilla-García

González‐Cano

et al. 2013

J Pharmacol Exp Ther

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We evaluated the effects of s 1 -receptor inhibition on m-opioidinduced mechanical antinociception and constipation. s 1 -Knockout mice exhibited marked mechanical antinociception in response to several m-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral m-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective A peripheral role for s 1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, s 1 -receptor inhibition did not alter fentanyl-or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, s 1 -receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral m-opioid analgesia without affecting opioidinduced constipation.

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Section: Modulation Of Peripheral M-opioidsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 94%

Section: Modulation Of Peripheral M-opioid Analgesia By S 1 Receptorsmentioning

confidence: 99%

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Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Sánchez-Fernández

Montilla-García

González‐Cano

et al. 2013

J Pharmacol Exp Ther

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“…It thus provides a strong basis for the design of peripherally acting opiate analgesics devoid of centrally mediated side effects [71]. Other mu receptor populations that contribute to pain control and opiate analgesia, in neurons other than Nav1.8 neurons and for distinct pain modalities, remain to be characterized by genetic approaches.…”

Section: Discussionmentioning

confidence: 99%

Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

et al. 2013

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Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund’s Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain.

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“…Here we investigated the efficacy of the peripherally restricted, non-addictive opioid loperamide [ 28 , 29 ]. Loperamide is an opioid that does not cross the blood brain barrier and is one of the few opioids that is non-addictive [ 30 ]. It is best known for its use as an antidiarrheal medication, binding mu opioid receptors in the gastrointestinal system and causing constipation [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

A Mouse Model of Chronic Pancreatitis Induced by an Alcohol and High Fat Diet

Clinkinbeard

Kline

Zhang

et al. 2017

TOPAINJ

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Background/Aims: Study of acute pancreatitis in chemically-induced rodent models has provided useful data; models of alcoholic chronic pancreatitis have not been available in mice. The aim of the present study was to characterize a mouse model of chronic pancreatitis induced solely with an alcohol and high fat (AHF) diet. Methods: Mice were fed a liquid high fat diet containing 6% alcohol as well as a high fat supplement (57% total dietary fat) over a period of five months or as control, normal chow ad libitum. Pain related measures utilized as an index of pain included mechanical sensitivity of the hind paws determined using von Frey filaments and a smooth/rough textured plate. A modified hotplate test contributed information about higher order behavioral responses to visceral hypersensitivity. Mice underwent mechanical and thermal testing both with and without pharmacological treatment with a peripherally restricted μ-opioid receptor agonist, loperamide. Results: Mice on the AHF diet exhibited mechanical and heat hypersensitivity as well as fibrotic histology indicative of chronic pancreatitis. Low dose, peripherally restricted opiate loperamide attenuated both mechanical and heat hypersensitivity. Conclusion: Mice fed an alcohol and high fat diet develop histology consistent with chronic pancreatitis as well as opioid sensitive mechanical and heat hypersensitivity.

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Dissecting the relative contribution of central versus peripheral opioid analgesia: Are the analgesic and adverse effects of opioids inseparable?

Cited by 4 publications

References 20 publications

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

A Mouse Model of Chronic Pancreatitis Induced by an Alcohol and High Fat Diet

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Dissecting the relative contribution of central versus peripheral opioid analgesia: Are the analgesic and adverse effects of opioids inseparable?

Cited by 4 publications

References 20 publications

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

A Mouse Model of Chronic Pancreatitis Induced by an Alcohol and High Fat Diet

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Product

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Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors