Abstract
Chronic pain is a major health problem, affecting 10–30% of the population in developed countries. While chronic pain is defined as “a persistent complaint of pain lasting for more than the usual period for recovery,” recently accumulated lines of evidence based on human brain imaging have revealed that chronic pain is not simply a sustained state of nociception, but rather an allostatic state established through gradually progressing plastic changes in the central nervous system. To visualize the brain activity associated with spontaneously occurring pain during the shift from acute to chronic pain under anesthetic-free conditions, we used manganese-enhanced magnetic resonance imaging (MEMRI) with a 9.4-T scanner to visualize neural activity-dependent accumulation of manganese in the brains of mice with hind paw inflammation. Time-differential analysis between 2- and 6-h after formalin injection to the left hind paw revealed a significantly increased MEMRI signal in various brain areas, including the right insular cortex, right nucleus accumbens, right globus pallidus, bilateral caudate putamen, right primary/secondary somatosensory cortex, bilateral thalamus, right amygdala, bilateral substantial nigra, and left ventral tegmental area. To analyze the role of the right amygdala in these post-formalin MEMRI signals, we repeatedly inhibited right amygdala neurons during this 2–6-h period using the “designer receptors exclusively activated by designer drugs” (DREADD) technique. Pharmacological activation of inhibitory DREADDs expressed in the right amygdala significantly attenuated MEMRI signals in the bilateral infralimbic cortex, bilateral nucleus accumbens, bilateral caudate putamen, right globus pallidus, bilateral ventral tegmental area, and bilateral substantia nigra, suggesting that the inflammatory pain-associated activation of these structures depends on the activity of the right amygdala and DREADD-expressing adjacent structures. In summary, the combined use of DREADD and MEMRI is a promising approach for revealing regions associated with spontaneous pain-associated brain activities and their causal relationships.
Highlights
Chronic pain is a major health problem, affecting 10–30% of the population in developed countries (Breivik et al, 2006; Hague and Shenker, 2014; Nakamura et al, 2014; Henschke et al, 2015)
Spontaneous pain is a hallmark of chronic pain symptoms such as those associated with fibromyalgia (Ichesco et al, 2014), arthritis (Kulkarni et al, 2007), the postoperative period (Simanski et al, 2014), and postherpetic neuralgia (Geha et al, 2007)
The formalin-treated mice did not show any more of these behavioral signs. This formalin-inflammation model shows bilateral tactile allodynia as well as augmented brain expression of phosphorylated extracellular signal-regulated kinase 3–6 h after the injection (Carrasquillo and Gereau, 2007; Shinohara et al, 2017), which leads to central plastic changes at 24 h (Adedoyin et al, 2010; Sugimura et al, 2016) and neuropathic pain-like phenotypes (Salinas-Abarca et al, 2017)
Summary
Chronic pain is a major health problem, affecting 10–30% of the population in developed countries (Breivik et al, 2006; Hague and Shenker, 2014; Nakamura et al, 2014; Henschke et al, 2015). Chronic pain is defined as “a persistent complaint of pain lasting for more than the usual period for recovery (usually 3 months)” (Jacobson and Mariano, 2001), recently accumulated lines of evidence obtained by human brain imaging have revealed that chronic pain is not a sustained state of nociception, but rather an allostatic state established through plastic and (mal)adaptive changes in the central nervous system (Melzack, 1999; Tracey and Mantyh, 2007; Price et al, 2018). Spontaneous pain is a hallmark of chronic pain symptoms such as those associated with fibromyalgia (Ichesco et al, 2014), arthritis (Kulkarni et al, 2007), the postoperative period (Simanski et al, 2014), and postherpetic neuralgia (Geha et al, 2007). The de novo establishment of aberrant brain activity through plastic changes in pain-associated brain regions is proposed to underlie the spontaneous pain (Apkarian et al, 2011; Price et al, 2018). Despite its devastating impact on the daily life of the patients, the mechanism underlying spontaneous pain in chronic pain patients as well as in animal models of persistent pain remains undetermined
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