Role of Na<sup>+</sup>,K<sup>+</sup>-ATPase in Morphine-Induced Antinociception

Masocha, Willias; Horváth, Gyöngyi; Agil, Ahmad; Ocaña, María; Pozo, Esperanza Del; Szikszay, Margit; Baeyens, José M.

doi:10.1124/jpet.103.052977

Cited by 25 publications

(12 citation statements)

References 33 publications

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“…Enzyme stimulation was present in all weaned groups with morphine sulfate doses. These results agree with the studies performed by Masocha et al [23,24] whose findings indicate that the activation of Na + , K + -ATPase plays a role in the antinociceptive effect of morphine, while in adult rats the Na + , K + -ATPase activity decreased. These results agree with Brase et al [25], whom suggest that morphine-induced increases the intracellular sodium in brain and decreases Na + , K + -ATPase activity, indicating that the development of tolerance may be accompanied by changes in the disposition of sodium.…”

Section: Discussionsupporting

confidence: 95%

Assessment of Oxidative Damage Induced by Acute Doses of Morphine Sulfate in Postnatal and Adult Rat Brain

et al. 2006

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The aim of the present study is to evaluate the oxidative damage in rats of different ages. Weaned rats of 25 g and adults of 300 g were used in groups of 6, a single i.p. dose of morphine sulfate of 3, 6 or 12 mg/kg was administered. All animals were sacrificed to measure GSH and 5-HT levels in brain by liquid chromatography, as well as Na(+), K(+)-ATPase and total ATPase enzymatic activity. 5-HT levels decreased significantly (p < 0.05) in adult animals that received 3 and 6 mg morphine. Na(+), K(+)-ATPase activity increased significantly (p < 0.05) in all groups of weaned animals. In adult animals, Na(+), K(+)-ATPase and total ATPase partially diminished. GSH levels diminished significantly (p < 0.05) both in weaned and in adult groups. The results indicate age-induced changes in cellular regulation and biochemical responses to oxidative stress induced by morphine.

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Section: Discussionsupporting

confidence: 95%

Assessment of Oxidative Damage Induced by Acute Doses of Morphine Sulfate in Postnatal and Adult Rat Brain

et al. 2006

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“…The complex ofopioid receptor and G i/o works by multiple mechanisms to inhibit neural pain impulses, thereby decreasing pain sensations in the brain [101,102]. EM-1 and morphine have been shown to stimulate Na + /K + -ATPase activity in vitro [103]. …”

Section: Endomorphin-1 Stimulates the -Opioid Receptor And Na + /K + mentioning

confidence: 99%

Glial dysfunction and persistent neuropathic postsurgical pain

Block

2016

Scandinavian Journal of Pain

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AbstractBackgroundAcute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10–50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosen-sory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed.A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron–glial interaction that causes enhanced and prolonged pain transmission.AimThis topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain.MethodRelevant literature was searched for in PubMed.Results Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocyte dysfunction can be experimentally restored using the combined actions of a μ–opioid receptor agonist, a μ–opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons. ConclusionSurgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission.ImplicationsLarger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.

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“…NKA is regulated indirectly by neurotransmitters through receptor-mediated signaling pathways, and is therefore involved in many physiological and pharmacological functions, including opioid receptor-mediated morphine analgesia [28,29]. Some neurotransmitters can induce the phosphorylation of the α subunit through stimulating protein kinase A or C, thereby modulating the transport properties of NKA [4,30].…”

Section: Fxyd2 Mediates a Distinct Mechanism For Regulating The Activmentioning

confidence: 99%

FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation

Feng

Cai

et al. 2015

Cell Res

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Na+ ,K + -ATPase (NKA) is required to generate the resting membrane potential in neurons. Nociceptive afferent neurons express not only the α and β subunits of NKA but also the γ subunit FXYD2. However, the neural function of FXYD2 is unknown. The present study shows that FXYD2 in nociceptive neurons is necessary for maintaining the mechanical allodynia induced by peripheral inflammation. FXYD2 interacted with α1NKA and negatively regulated the NKA activity, depolarizing the membrane potential of nociceptive neurons. Mechanical allodynia initiated in FXYD2-deficient mice was abolished 4 days after inflammation, whereas it persisted for at least 3 weeks in wild-type mice. Importantly, the FXYD2/α1NKA interaction gradually increased after inflammation and peaked on day 4 post inflammation, resulting in reduction of NKA activity, depolarization of neuron membrane and facilitation of excitatory afferent neurotransmission. Thus, the increased FXYD2 activity may be a fundamental mechanism underlying the persistent hypersensitivity to pain induced by inflammation. Keywords: FXYD2; Na

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Role of Na⁺,K⁺-ATPase in Morphine-Induced Antinociception

Abstract: We evaluated the modulation by Na ϩ ,K ϩ -ATPase inhibitors of morphine-induced antinociception in the tail-flick test and [ 3

Cited by 25 publications

References 33 publications

Assessment of Oxidative Damage Induced by Acute Doses of Morphine Sulfate in Postnatal and Adult Rat Brain

Assessment of Oxidative Damage Induced by Acute Doses of Morphine Sulfate in Postnatal and Adult Rat Brain

Glial dysfunction and persistent neuropathic postsurgical pain

FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation

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Role of Na+,K+-ATPase in Morphine-Induced Antinociception

Abstract: We evaluated the modulation by Na ϩ ,K ϩ -ATPase inhibitors of morphine-induced antinociception in the tail-flick test and [ 3

Cited by 25 publications

References 33 publications

Assessment of Oxidative Damage Induced by Acute Doses of Morphine Sulfate in Postnatal and Adult Rat Brain

Assessment of Oxidative Damage Induced by Acute Doses of Morphine Sulfate in Postnatal and Adult Rat Brain

Glial dysfunction and persistent neuropathic postsurgical pain

FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation

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Role of Na⁺,K⁺-ATPase in Morphine-Induced Antinociception