Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors

Tejada, Miguel; Montilla-García, Ángeles; Sánchez-Fernández, Cristina; Entrena, José Manuel; Perazzoli, Gloria; Baeyens, José M.; Cobos, Enrique J.

doi:10.1007/s00213-014-3524-3

Cited by 51 publications

(49 citation statements)

References 48 publications

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“…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. 1 A and B, respectively) and are consistent with our previous study (14). In contrast to the sigma-1 antagonists, the selective sigma-1 agonist PRE-084 had no effect on the response latency in mice without inflammation or in mice with inflammation stimulated with either pressure or heat ( Fig.…”

Section: Resultssupporting

confidence: 91%

“…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%

“…Paw inflammation was induced with an i.pl. injection of carrageenan (14) to female CD-1 mice. Paw edema was measured with a plethysmometer (14).…”

Section: Methodsmentioning

confidence: 99%

“…injection of carrageenan (14) to female CD-1 mice. Paw edema was measured with a plethysmometer (14). Experiments were performed during acute (3 h) or sustained (5 d) inflammation.…”

Section: Methodsmentioning

confidence: 99%

“…The role of sigma-1 receptors in pathological pain, apart from neuropathic pain, has been less well explored, but recent reports have shown that sigma-1 antagonism can ameliorate inflammatory hyperalgesia (14). Immune cells that infiltrate inflamed tissue produce and release algogenic chemicals that participate in the sensitization of nociceptors; thus, immune cells promote pain during inflammation (15).…”

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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: 91%

Section: Resultssupporting

confidence: 90%

“…Paw inflammation was induced with an i.pl. injection of carrageenan (14) to female CD-1 mice. Paw edema was measured with a plethysmometer (14).…”

Section: Methodsmentioning

confidence: 99%

“…injection of carrageenan (14) to female CD-1 mice. Paw edema was measured with a plethysmometer (14). Experiments were performed during acute (3 h) or sustained (5 d) inflammation.…”

Section: Methodsmentioning

confidence: 99%

mentioning

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 Receptor Expression in DRG Neurons During a Carrageenan‐Provoked Inflammation

Jerčić

Kostić

Uljević

et al. 2019

The Anatomical Record

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Sigma 1 receptor (σ1R) is a non-opioid receptor that modulates pain perception and is strongly expressed in dorsal root ganglion (DRG) neurons. We studied the changes in the expression of σ1R in different subpopulations of DRG neurons during the first 48 hr in a carrageenaninduced inflammation rat model, with σ1R being a possible base for the development of neuropathic pain after inflammation. Twenty Sprague Dawley rats were divided into five groups (N = 4 in each group): the control (C) group was sacrificed immediately; all other animals received an intraplantar injection of 0.1 mL 2% carrageenan and were sacrificed in 6, 12, 24 or 48 hr after the injection and DRGs were collected and processed for immunohistochemistry. σ1R fluorescence intensity decreased slightly but significantly in up to 24 hr post-carrageenan injection in all subpopulations of DRG neurons (ib4+; ib4− medium, ib4− large and ib4− in total; P < 0.05 -P < 0.001), with the exception of the ib4− small neurons (<25 μm; P > 0.05). This decrement was followed by a subsequent increase in σ1R fluorescence intensity 48 hr after the plantar carrageenan injection (P < 0.05 -P < 0.0001). The same trend was also observed in the CGRP+ population of the DRG neurons, in the total population as well as in the CGRP+ small (<25 μm) and larger CGRP (>25 μm) sub-populations (P < 0.05 -P < 0.001). The presented results may contribute to further understanding of role of σ1R in the development of peripheral sensitization during inflammation. They may also be valuable for the therapeutic application of σ1R antagonists, particularly in the adjustment of the ABBREVIATIONS: CCI = chronic constriction injury; CFA = complete Freund adjuvant; CGRP = calcitonin gene-related peptide; DRG = dorsal root ganglion; ER = endoplasmic reticulum; ib4 = isolectin B4; IP3 = inositol 1,4,5-triphosphate; KO = knockout; PBS = phosphate-buffered saline; SNL = spinal nerve ligation; σ1R = sigma 1 receptor Grant sponsor: Ministarstvo Znanosti, Obrazovanja i Sporta.

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Role of peripheral sigma‐1 receptors in ischaemic pain: Potential interactions with ASIC and P2X receptors

Kwon

Roh

Yoon

et al. 2015

European Journal of Pain

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Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors

Abstract: σ1 receptors play a major role in inflammatory hyperalgesia. Targeting σ1 receptors in the inflamed tissue may be useful for the treatment of inflammatory pain.

Cited by 51 publications

References 48 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

Sigma‐1 Receptor Expression in DRG Neurons During a Carrageenan‐Provoked Inflammation

Role of peripheral sigma‐1 receptors in ischaemic pain: Potential interactions with ASIC and P2X receptors

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