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

Muralidharan, Arjun; Sotocinal, Susana G.; Austin, Jean-Sébastien; Mogil, Jeffrey S.

doi:10.1097/pr9.0000000000000824

Cited by 18 publications

(13 citation statements)

References 26 publications

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“…This conclusion might be confounded by the fact that each time point represents a separate cohort of mice. Hence, we also confirmed the longer-lasting allodynia in male versus female mice in a separate experiment using a longitudinal design in which mice were tested repeatedly for over 5 months after SNI/sham ( Supplemental Figure 1 ; supplemental material available online with this article; https://doi.org/10.1172/JCI151817DS1 ), and again in a recently published experiment in mice at 12 months after surgery ( 20 ).…”

Section: Resultssupporting

confidence: 77%

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Muralidharan¹,

Sotocinal²,

Yousefpour³

et al. 2022

Journal of Clinical Investigation

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Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus ( TP53 ) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.

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Section: Resultssupporting

confidence: 77%

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Muralidharan¹,

Sotocinal²,

Yousefpour³

et al. 2022

Journal of Clinical Investigation

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“…SNI led to pronounced mechanical allodynia as indicated by robust reductions in paw withdrawal thresholds. No significant sex differences in basal or SNI-induced thresholds were observed, consistent with previous studies using the SNI model (Muralidharan et al, 2020;Sheehan et al, 2021) (Figure 1A). EtOH administration fully reversed mechanical allodynia in SNI mice in the von Frey assay, albeit at different doses and timepoints in males and females.…”

Section: Discussionsupporting

confidence: 92%

Effects of ethanol on mechanical allodynia and dynamic weight bearing in male and female mice with spared nerve injury

Nothem

Wickman

Giacometti

et al. 2022

Alcohol: Clinical and Experimental Research

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Background Men and women with chronic pain report increased alcohol use and are more likely to be diagnosed with alcohol use disorder. The relationship between alcohol use and pain is bidirectional. Alcohol is used as an analgesic, but chronic alcohol intake increases pain. Sex differences in the relationship between chronic pain and alcohol are reported in the clinical and preclinical literature, but due to this bidirectional relationship, it is challenging to investigate the mechanisms that contribute to these differences. Thus, animal models of chronic pain are needed to characterize the efficacy of ethanol as an analgesic in males and females. The current experiments tested the hypothesis that ethanol differentially reduces pain behaviors in male and female mice in chronic neuropathic pain. Methods The spared nerve injury (SNI) model was used to investigate the analgesic effects of multiple doses of ethanol (0.5, 1, 2, g/kg i.p.) in male and female mice using von Frey and dynamic weight‐bearing (DWB) assays. Results In both male and female mice, SNI led to robust allodynia and shifts in dynamic weight bearing. In male SNI mice, all three doses of ethanol fully reversed mechanical allodynia and shifts in DWB. In SNI females, only the highest dose (2.0 g/kg) was fully antiallodynic in the von Frey assay, while shifts in weight bearing were reversed at the 1.0 and 2.0 g/kg doses. The differences between male and females were not due to lower blood ethanol concentrations in female mice. Conclusion These data indicate that while ethanol has antiallodynic and antinociceptive effects in male and female mice, the doses and time course of these effects are distinct. Studies investigating the relationship between pain and ethanol exposure in mice should consider sex as a key variable. These data also inform reported sex differences in rodent models of chronic pain and in chronic pain patients.

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“…Alternatively, continuous infusion via a controlled pump for 4-6 days has also been trialled to treat different chronic pain syndromes 34,35 . However, it should be recognized that our current study only used young male mice, many pain phenotypes differ between sexes with females typically reporting greater pain responses 36,37 . A further limitation of our study regards translating efficacy from a single pain model in one mouse strain to humans; for example, pregabalin has larger and broader analgesic effects in rodent chronic pain models than observed clinically 38 .…”

Section: Discussionmentioning

confidence: 99%

Controlled activation of cortical astrocytes modulates neuropathic pain-like behaviour

et al. 2022

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Chronic pain is a major public health problem that currently lacks effective treatment options. Here, a method that can modulate chronic pain-like behaviour induced by nerve injury in mice is described. By combining a transient nerve block to inhibit noxious afferent input from injured peripheral nerves, with concurrent activation of astrocytes in the somatosensory cortex (S1) by either low intensity transcranial direct current stimulation (tDCS) or via the chemogenetic DREADD system, we could reverse allodynia-like behaviour previously established by partial sciatic nerve ligation (PSL). Such activation of astrocytes initiated spine plasticity to reduce those synapses formed shortly after PSL. This reversal from allodynia-like behaviour persisted well beyond the active treatment period. Thus, our study demonstrates a robust and potentially translational approach for modulating pain, that capitalizes on the interplay between noxious afferents, sensitized central neuronal circuits, and astrocyte-activation induced synaptic plasticity.

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

Abstract: We find that female mice display no allodynia 10 months after nerve injury, and pregabalin loses its effectiveness after that delay, and in middle-aged mice.

Cited by 18 publications

References 26 publications

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Effects of ethanol on mechanical allodynia and dynamic weight bearing in male and female mice with spared nerve injury

Controlled activation of cortical astrocytes modulates neuropathic pain-like behaviour

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