Research reportAquaporin 4 knockout increases complete freund's adjuvant-induced spinal central sensitization
Introduction
Pain is an unpleasant subjective feeling and/or emotional experience associated with actual or potential tissue damages (Sandkühler, 2009). At present, the conduction pathway of pain has been identified, but the modulating mechanisms of pain remain elusive (Ji et al., 2016).
Transmission of nociception is controlled by numerous factors, of which glutamate (Glu), an excitatory neurotransmitter, plays a crucial role in the formation and persistence of pain (Osikowicz et al., 2013). It has become increasingly clear that strengthening of glutamatergic sensory synapses is one of major contributors to central sensitization (Dong et al., 2012; Gogas, 2005; Kanai and Hediger, 2003; Larsson and Broman, 2011). For instance, pharmacological inhibition of spinal glutamate transporters (GluTs) aggravates persistent pain (Ramos et al., 2010; Sung et al., 2003), whereas enhancing expression of GluTs by viral gene transfer mitigates chronic pain (Lin et al., 2011; Maeda et al., 2008). Therefore, modulation of glutamatergic transmission could potentially serve as a prospective therapeutic approach for the management of chronic pain (Gegelashvili and Bjerrum, 2019).
Astrocytes have been shown to modulate glutamatergic neurotransmission by Glu uptake from the synaptic cleft via their membrane-specific GluTs, including glutamate transporter 1 (GLT1) and glutamate aspartate transporter (GLAST) (excitatory amino acid transporter 1 and 2 in humans) (Pajarillo et al., 2019). Spinal astrocytes can be activated by excessive Glu released from primary sensory terminals of dorsal root ganglion (DRG) neurons and nociceptive interneurons in the spinal cord after nerve injury or peripheral inflammation (Sung et al., 2003). Therefore, enhancing astrocyte reuptake of Glu may be an effective approach for treatments of chronic pain (Gao and Ji, 2010; Ren, 2010; Yousuf and Kerr, 2016; Jin et al., 2013).
Aquaporin 4 (AQP4) is a subtype of AQPs found in the highest quantity within the central nervous system (CNS). It is specifically localized to perivascular endfeet of astrocytes, as well as lateral and basal membranes of ependymal epithelium cells (Nielsen et al., 1997). AQP4 is responsible for maintaining the homeostasis of water and ions in the CNS (Nagelhus and Ottersen, 2013). Moreover, AQP4 is implicated in regulating astrocyte uptake of Glu (Zeng et al., 2007). Early studies reported that Glu increases astrocyte water permeability, with AQP4 being the molecular target for this effect (Gunnarson et al., 2008). Further studies have revealed that AQP4 deficiency impairs hippocampal long-term potentiation, with high extracellular Glu concentration and N-methyl-d-aspartate (NMDA) receptor-mediated currents in hippocampal dentate gyrus region (Yang et al., 2013). This suggests that AQP4-mediated astrocyte reuptake of Glu is involved in the modulation of signaling pain. In the present study, we examined this possibility in a mouse model of peripheral inflammation, utilizing intraplantar injection of complete Freund's adjuvant (CFA).
Section snippets
Animals
The AQP4 gene knockout (KO) mice with a CD1 genetic background were created in our laboratory (Fan et al., 2005). Three-month old male AQP4 KO mice and wild-type (WT) mice were randomly divided into CFA-injected group and saline-injected group. The animals were housed under standard laboratory conditions, with ad libitum access to food and water. The experiment was approved by the Animal Ethical and Welfare Committee of Nanjing Medical University (NMU) and conducted in accordance with the
AQP4 deficiency increases CFA-induced mechanical allodynia and thermal hyperalgesia
The nociceptive thresholds of mechanical and thermal stimuli were comparable between AQP4 KO and WT mice at the baseline condition. Intraplantar injection of CFA reduced paw withdrawal thresholds to non-noxious mechanical stimuli in the both mouse genotypes at day 1 and day 3 (Treatment effect: F1,44 = 53.459, p < 0.001, Genotype effect: F1,44 = 1.096, p = 0.312; repeated-measures ANOVA, n = 12 per group). However, at day 7, 9 and 11, the thresholds were significantly lower in the AQP4 KO-CFA
Discussion
Chronic or persistent pain is one of the primary causes of physical and mental impairments, seriously reducing the quality of life and work efficiency (Mazereeuw et al., 2018). There are a variety of drugs, and non-pharmacological approaches, used to relieve pain (Vorobeychik et al., 2011). However, the long-term use of analgesic drugs, especially opioids, is highly addictive, and also causes serious side effects including respiratory depression and even death (Stein, 2018). Therefore, it is
Author statement
All of the authors seriously declare that neither the submitted paper nor any similar paper, either in whole or in part, has been or will be submitted to or published in any other primary scientific journal. The experiment was approved by the Animal Ethical and Welfare Committee of Nanjing Medical University (NMU) and conducted in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of NMU. All of the authors are aware of and agree to the content of the
Declaration of Competing Interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Acknowledgements
This work was supported by a grant from the Natural Science Foundation of Jiangsu Educational Department, China (09KJA310003).
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2021, Journal of EthnopharmacologyCitation Excerpt :EOAE-D and EOAE-B were assayed against the CFA-induced mechanical hyperalgesia, cold sensitivity, and paw oedema induced by CFA (Fig. 7). Complete Freud's adjuvant (CFA) is a product widely used in biological research (Stein et al., 1988, Wang et al., 2020) to induce intense immunological and inflammatory responses and central and peripheral sensitization (for example, mechanical and thermal hyperalgesia) in rodents. The oral acute treatment with EOAE-D and EOAE-B at 30 mg/kg significantly inhibited mechanical hyperalgesia (Fig. 7A) and oedema formation (Fig. 7C) compared to those of the control group at all observed time points.
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2020, Behavioural Brain ResearchCitation Excerpt :The development of pain was accompanied by a significant increase in spinal AQP4 expression, astrocyte activation, and a return of microglial activation to baseline levels. Recently, Wang et al. reported that AQP4 knockout mice intensified, rather than attenuated, CFA-induced mechanical allodynia and thermal hyperalgesia [42], which is inconsistent with our results. We speculate that the discrepancy might be due to the different genetic background of the mice, given that genetic background is well known to play an important role in gene functions.
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These authors contributed equally to this work.