Roles of AMPK and Its Downstream Signals in Pain Regulation

Pain is an unpleasant sensory and emotional state that decreases quality of life. A metabolic sensor, adenosine monophosphate-activated protein kinase (AMPK), which is ubiquitously expressed in mammalian cells, has recently attracted interest as a new target of pain research. Abnormal AMPK expression and function in the peripheral and central nervous systems are associated with various types of pain. AMPK and its downstream kinases participate in the regulation of neuron excitability, neuroinflammation and axonal and myelin regeneration. Numerous AMPK activators have reduced pain behavior in animal models. The current understanding of pain has been deepened by AMPK research, but certain issues, such as the interactions of AMPK at each step of pain regulation, await further investigation. This review examines the roles of AMPK and its downstream kinases in neurons and non-neuronal cells, as well as their contribution to pain regulation.

Corticotropin-releasing factor neurons in the bed nucleus of the stria terminalis exhibit sex-specific pain encoding in mice

The bed nucleus of the stria terminalis (BNST) plays an emerging role in pain regulation. Pharmacological studies have found that inhibiting corticotropin-releasing factor (CRF) signaling in the BNST can selectively mitigate the sensory and affective-motivational components of pain. However, mechanistic insight on the source of CRF that drives BNST responses to these harmful experiences remains unknown. In the present study, we used a series of genetic approaches to show that CRF in the BNST is engaged in the processing and modulation of pain. We conducted cell-type specific in vivo calcium imaging in CRF-Cre mice and found robust and synchronized recruitment of BNSTCRF neurons during acute exposures to noxious heat. Distinct patterns of recruitment were observed by sex, as the magnitude and timing of heat responsive activity in BNSTCRF neurons differed for male and female mice. We then used a viral approach in Floxed-CRF mice to selectively reduce CRF expression in the BNST and found it decreased nociceptive sensitivity for both sexes and increased paw attending for females. Together, these findings reveal that CRF in the BNST influences multiple facets of the pain experience to impact the sex-specific expression of pain-related behaviors.

Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability

Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain’s descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.

Research progress on the mechanism of orexin in pain regulation in different brain regions

Orexin is a neuropeptide that is primarily synthesized and secreted by the lateral hypothalamus (LH) and includes two substances derived from the same precursor (orexin A [OXA] and orexin B [OXB]). Studies have shown that orexin is not only involved in the regulation of eating, the sleep–wake cycle, and energy metabolism, but also closely associated with various physiological functions, such as cardiovascular control, reproduction, stress, reward, addiction, and the modulation of pain transmission. At present, studies that have been performed both domestically and abroad have confirmed that orexin and its receptors are closely associated with pain regulation. In this article, the research progress on acute pain regulation involving orexin is reviewed.

Electroacupuncture Attenuates CFA-Induced Inflammatory Pain by Regulating CaMKII

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that is ubiquitously distributed in the central and peripheral nervous systems. Moreover, its phosphorylated protein (P-CaMKII) is involved in memory, mood, and pain regulation in the anterior cingulate cortex (ACC). Electroacupuncture (EA) is a traditional Chinese therapeutic technique that can effectively treat chronic inflammatory pain. However, the CaMKII-GluA1 role in EA analgesia in the ACC remains unclear. This study investigated the role of P-CaMKII and P-GluA1 in a mouse model of inflammatory pain induced by complete Freund’s adjuvant (CFA). There were increased P-CaMKII and P-GluA1 levels in the ACC. We found that intracerebroventricular injection of KN93, a CaMKII inhibitor, as well as EA stimulation, attenuated complete Freund’s adjuvant-induced pain behavior. Further, EA increased pCaMKII-PICK1 complex (abbreviated as C-P complex) levels. Our findings demonstrate that EA inhibits inflammatory pain by inhibiting CaMKII-GluA1 phosphorylation. P-CaMKII is involved in EA analgesia as the pCaMKII-PICK1 complex.

Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain

Adenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A1, A2A, A2B, and A3 adenosine receptors (ARs). In recent years, extensive progress has been made to elucidate the role of adenosine in pain regulation. Most of the antinociceptive effects of adenosine are dependent upon A1AR activation located at peripheral, spinal, and supraspinal sites. The role of A2AAR and A2BAR is more controversial since their activation has both pro- and anti-nociceptive effects. A3AR agonists are emerging as promising candidates for neuropathic pain. Although their therapeutic potential has been demonstrated in diverse preclinical studies, no AR ligands have so far reached the market. To date, novel pharmacological approaches such as adenosine regulating agents and allosteric modulators have been proposed to improve efficacy and limit side effects enhancing the effect of endogenous adenosine. This review aims to provide an overview of the therapeutic potential of ligands interacting with ARs and the adenosinergic system for the treatment of acute and chronic pain.