Effects of local and spinal administrations of mu-opioids on postoperative pain in aged vs adult mice

Mecklenburg, Jennifer; Patil, Mayur; Koek, Wouter; Akopian, Armen N.

doi:10.1097/pr9.0000000000000584

Cited by 8 publications

(4 citation statements)

References 48 publications

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“…With respect to response to analgesics, most of the available evidence in humans comes from studies of postoperative analgesic consumption (cf. Ref. 14 ), and in laboratory animals from studies of morphine inhibition of tail-flick or other reflexes (see Ref.…”

Section: Introductionmentioning

confidence: 99%

The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice

Muralidharan

Sotocinal

Austin

et al. 2020

PR9

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Section: Introductionmentioning

confidence: 99%

The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice

Muralidharan

Sotocinal

Austin

et al. 2020

PR9

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“…XYL, an α 2 -adrenergic agonist commonly used as a sedative and muscle relaxant in veterinary medicine, can modulate pain perception by reducing norepinephrine release (Kitano et al, 2019). DAMGO binds with high affinity to the µ-opioid receptor and is a synthetic analog of endogenous opioids with a strong morphine-like antinociceptive effect (Al-Khrasani et al, 2007; Mecklenburg et al, 2017). Furthermore, the AEA, XYL, and DAMGO antinociceptive profiles obtained in this study fit with good concordance with a four-parameter model, in which the effects were clearly saturable with steep correlation, indicating robust antinociceptive effects in the PGE 2 -induced hyperalgesia model.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive synergy in a peripheral hyperalgesia model: interplay of cannabinoidergic, adrenergic, and opioidergic systems and their antagonism

Lopes,

Santos-Silva,

Fonseca

et al. 2024

Preprint

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There is growing interest in co-administering know analgesics for pain management, to reduce side effects and maximize therapeutic effects by pharmacological synergism, defined as supra-additive effects to biological stimuli. This work aimed to evaluate, using isobolgraphic analysis, synergistic effects of three antinociceptive substances— anandamide (AEA), a cannabinoid CB1 receptor agonist; xylazine (XYL), an adrenergic α2-receptor agonist; and DAMGO, an µ-opioid receptor agonist—administered in binary doses in a prostaglandin E2 (PGE2)-induced peripheral pain model. Hyperalgesia was induced in Swiss male mice, and subsequently, animals were treated with binary agonist combinations administered to the hind paw. Mechanical nociceptive thresholds were measured using an algesimetric task, and the results obtained were compared with additive predicted effects. For AEA+XYL and AEA+DAMGO combinations, the observed effects were significantly greater than those predicted by Loewe’s additivity principles at all tested effect levels (10%, 30%, and 50% maximum possible effect, MPE). DAMGO+XYL combination showed significant synergistic effects at 10% and 30% MPE but not at 50% MPE. Confirming these findings, combination indexes (CI) for AEA+XYL and AEA+DAMGO were less than 1, indicating synergism, while CI for DAMGO+XYL was near 1, indicating additivity. Notably, single-system antagonism with either AM251, a CB1 antagonist, yohimbine, an α2C-receptor antagonist or naloxone, pan-opioid receptor antagonist, could prevent synergy or any analgesia at all for AEA+XYL and AEA+DAMGO. Furthermore, the binary agonist combinations did not produce systemic effects, sedation, or motor impairments. The results suggest synergistic antinociceptive effects for AEA+XYL and AEA+DAMGO, which are dependent on concomitant agonism upon known metabotropic receptors.

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“…Sample size calculations were based on our previous experience in RNA-seq and behavioral experiments on linear and inbred C57-black mice 29 , 70 . Accordingly, in behavioral experiments, we estimate that 6–8 mice will achieve > 80% statistical power to achieve P < 0.05 difference in measurement of hypersensitivity.…”

Section: Methodsmentioning

confidence: 99%

Associations of tissue damage induced inflammatory plasticity in masseter muscle with the resolution of chronic myalgia

Lindquist,

Shein,

Hovhannisyan

et al. 2023

Sci Rep

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Gene plasticity during myogenous temporomandibular disorder (TMDM) development is largely unknown. TMDM could be modeled by intramuscular inflammation or tissue damage. To model inflammation induced TMDM we injected complete Freund’s adjuvant (CFA) into masseter muscle (MM). To model tissue damage induced TMDM we injected extracellular matrix degrading collagenase type 2 (Col). CFA and Col produced distinct myalgia development trajectories. We performed bulk RNA-seq of MM to generate gene plasticity time course. CFA initiated TMDM (1d post-injection) was mainly linked to chemo-tacticity of monocytes and neutrophils. At CFA-induced hypersensitivity post-resolution (5d post-injection), tissue repair processes were pronounced, while inflammation was absent. Col (0.2U) produced acute hypersensitivity linked to tissue repair without inflammatory processes. Col (10U) generated prolonged hypersensitivity with inflammatory processes dominating initiation phase (1d). Pre-resolution phase (6d) was accompanied with acceleration of expressions for tissue repair and pro-inflammatory genes. Flow cytometry showed that immune processes in MM was associated with accumulations of macrophages, natural killer, dendritic and T-cells, further confirming our RNA-seq findings. Altogether, CFA and Col treatments induced different immune processes in MM. Importantly, TMDM resolution was preceded with muscle cell and extracellular matrix repairs, an elevation in immune system gene expressions and distinct immune cell accumulations in MM.

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Effects of local and spinal administrations of mu-opioids on postoperative pain in aged vs adult mice

Abstract: Supplemental Digital Content is Available in the Text.Baseline nociception is higher in adult mice. Mu-opioid postoperative hypersensitivity is age-dependent; aged mice are less sensitive to DAMGO, and more to higher buprenorphine doses.

Cited by 8 publications

References 48 publications

The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice

The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice

Antinociceptive synergy in a peripheral hyperalgesia model: interplay of cannabinoidergic, adrenergic, and opioidergic systems and their antagonism

Associations of tissue damage induced inflammatory plasticity in masseter muscle with the resolution of chronic myalgia

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