Potentiation of morphine-induced mechanical antinociception by σ1 receptor inhibition: Role of peripheral σ1 receptors

Sánchez-Fernández, Cristina; Nieto, Francisco R.; González‐Cano, Rafael; Artacho-Cordón, Antonia; Romero, Lucía; Montilla-García, Ángeles; Zamanillo, Daniel; Baeyens, José M.; Entrena, José Manuel; Cobos, Enrique J.

doi:10.1016/j.neuropharm.2013.03.002

Cited by 61 publications

(67 citation statements)

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“…S1 A and B). These results agree with both the known absence of effects of sigma-1 antagonism on nociceptive pain induced by mechanical or thermal stimuli (9,17) and the recently reported amelioration of inflammatory hyperalgesia by sigma-1 antagonism (14). Although the results for thermal and mechanical hyperalgesia were qualitatively equivalent, the doses of sigma-1 antagonists required to fully reverse thermal hypersensitivity were higher than those needed to reverse mechanical hyperalgesia ( Fig.…”

Section: Resultssupporting

confidence: 90%

“…The potentiation of opioid antinociception by sigma-1 antagonism was described in the early 1990s (7). Later studies showed that the enhancement of opioid antinociception by sigma-1 antagonism is produced at central levels (8) and is particularly prominent at peripheral levels (9,10). The marked potentiation of opioid antinociception by peripheral sigma-1 antagonism is consistent with its higher density in the dorsal root ganglion than in several central areas (10).…”

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confidence: 71%

“…1 E and F) stimuli, indicating that naloxone methiodide inhibits the effects of the sigma-1 antagonists in a noncompetitive manner. Naloxone methiodide does not bind to sigma-1 receptors (10), and conversely, the sigma-1 antagonists BD-1063 and S1RA do not bind to opioid receptors (9,17). However, sigma-1 receptors can form macromolecular complexes with opioid receptors to produce tonic inhibition of receptor functioning (12,13).…”

Section: Effects Of Sigma-1 Antagonists On Acute Inflammatory Hyperalmentioning

confidence: 99%

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Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Tejada

Montilla-García

Cronin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sigma-1 antagonism potentiates the antinociceptive effects of opioid drugs, so sigma-1 receptors constitute a biological brake to opioid drug-induced analgesia. The pathophysiological role of this process is unknown. We aimed to investigate whether sigma-1 antagonism reduces inflammatory pain through the disinhibition of the endogenous opioidergic system in mice. The selective sigma-1 antagonists BD-1063 and S1RA abolished mechanical and thermal hyperalgesia in mice with carrageenan-induced acute (3 h) inflammation. Sigma-1-mediated antihyperalgesia was reversed by the opioid antagonists naloxone and naloxone methiodide (a peripherally restricted naloxone analog) and by local administration at the inflamed site of monoclonal antibody 3-E7, which recognizes the pan-opioid sequence TyrGly-Gly-Phe at the N terminus of most endogenous opioid peptides (EOPs). Neutrophils expressed pro-opiomelanocortin, the precursor of β-endorphin (a known EOP), and constituted the majority of the acute immune infiltrate. β-endorphin levels increased in the inflamed paw, and this increase and the antihyperalgesic effects of sigma-1 antagonism were abolished by reducing the neutrophil load with in vivo administration of an anti-Ly6G antibody. The opioid-dependent sigma-1 antihyperalgesic effects were preserved 5 d after carrageenan administration, where macrophages/monocytes were found to express pro-opiomelanocortin and to now constitute the majority of the immune infiltrate. These results suggest that immune cells harboring EOPs are needed for the antihyperalgesic effects of sigma-1 antagonism during inflammation. In conclusion, sigma-1 receptors curtail immune-driven peripheral opioid analgesia, and sigma-1 antagonism produces local opioid analgesia by enhancing the action of EOPs of immune origin, maximizing the analgesic potential of immune cells that naturally accumulate in painful inflamed areas.sigma-1 receptors | inflammatory pain | endogenous opioid peptides | immune cells

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Section: Resultssupporting

confidence: 90%

mentioning

confidence: 71%

Section: Effects Of Sigma-1 Antagonists On Acute Inflammatory Hyperalmentioning

confidence: 99%

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Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Tejada

Montilla-García

Cronin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Inhibition of s 1 -receptor function either by the systemic administration of s 1 antagonists or by s 1 -receptor knockdown does not influence acute nociception per se (Cendán et al, 2005;De la Puente et al, 2009;Entrena et al, 2009b;Nieto et al, 2012;Romero et al, 2012;Sánchez-Fernández et al, 2013). However, s 1 inhibition is able to enhance opioid signaling (Kim et al, 2010) and to potentiate the antinociceptive effect of systemic opioids Pasternak, 1993, 1994;Marrazzo et al, 2011;Sánchez-Fernández et al, 2013;Vidal-Torres et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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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“…One of these is to administer an adjuvant drug with synergistic analgesic effects in order to minimize the dose of the opioid while maintaining acceptable levels of analgesia as combination of non-steroidal antiinflammatory drugs, anticonvulsants, or sodium-channel blockers with opioids (1,2). The administration of a2 (3), 5-HT 7 (4) agonists, NMDA (5), or s antagonists (6) can potentiate morphine analgesia. However, clinical trials have sometimes found contradictory results and this approach may have some adverse clinical implications (7).…”

Section: Introductionmentioning

confidence: 99%

PKC-Mediated Potentiation of Morphine Analgesia by St. John’s Wort in Rodents and Humans

Galeotti

Farzad²,

Bianchi

et al. 2014

J Pharmacol Sci

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Abstract. Our purpose was to combine the use of morphine with clinically available inhibitors of protein kinase C (PKC), finally potentiating morphine analgesia in humans. Thermal tests were performed in rodents and humans previously administered with acute or chronic morphine combined or not with increasing doses of the PKC-blocker St. John's Wort (SJW) or its main component hypericin. Phosphorylation of the g subunit of PKC enzyme was assayed by western blotting in the periaqueductal grey matter (PAG) from rodents co-administered with morphine and hypericin and was prevented in rodent PAG by SJW or hypericin co-administration with morphine, inducing a potentiation of morphine analgesia in thermal pain. The score of pain assessment in healthy volunteers were decreased by 40% when morphine was co-administered with SJW at a dose largely below those used to obtain an antidepressant or analgesic effect in both rodents and humans. The SJW/hypericin potentiating effect lasted in time and preserved morphine analgesia in tolerant mice. Our findings indicate that, in clinical practice, SJW could reduce the dose of morphine obtaining the same analgesic effect. Therefore, SJW and one of its main components, hypericin, appear ideal to potentiate morphine-induced analgesia.

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Potentiation of morphine-induced mechanical antinociception by σ1 receptor inhibition: Role of peripheral σ1 receptors

Cited by 61 publications

References 50 publications

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

PKC-Mediated Potentiation of Morphine Analgesia by St. John’s Wort in Rodents and Humans

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Potentiation of morphine-induced mechanical antinociception by σ1 receptor inhibition: Role of peripheral σ1 receptors

Cited by 61 publications

References 50 publications

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

PKC-Mediated Potentiation of Morphine Analgesia by St. John’s Wort in Rodents and Humans

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Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors