Neuroscience
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Chronic pain conditions are multifactorial disorders with a high frequency in the population. Their pathophysiology is often unclear, and treatment is inefficient. During the last 20years, genetic linkage analysis and association studies have made considerable strides toward identifying key molecular contributors to the onset and maintenance of chronic pain. ⋯ In rare familial monogenic pain conditions several strong-effect mutations have been identified. In contrast, the genetic landscape of common chronic pain conditions suggests minor contributions from a large number of single nucleotide polymorphisms representing different functional pathways. A comprehensive survey of up-to-date genetic association results reveals migraine and musculoskeletal pain to be the most investigated chronic pain disorders, in which nearly half of identified genetic variability alters neurotransmission pathways.
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Animal and human studies have consistently demonstrated that cortical regions are important for pain perception and pain-related emotional changes. Studies of the anterior cingulate cortex (ACC) have shown that adult cortical synapses can be modified after peripheral injuries, and long-term changes at synaptic level may contribute to long-lasting suffering in patients. ⋯ Inhibiting IC LTP reduces behavioral sensitization caused by injury. LTP of glutamatergic transmission in pain related cortical areas serves as a key mechanism for chronic pain.
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The midbrain dopamine center comprises a key network for reward, salience, motivation, and mood. Evidence from various clinical and preclinical settings points to the midbrain dopamine circuit as an important modulator of pain perception and pain-induced anxiety and depression. This review summarizes recent findings that shed light to the neuroanatomical, electrophysiological and molecular adaptations that chronic pain conditions promote in the mesolimbic dopamine system. ⋯ Here, we discuss recent findings on the mechanisms involved in the perception of chronic pain, in pain-induced anxiety and depression, as well as in pain-killer addiction vulnerability. Several new studies also show that the mesolimbic dopamine circuit potently modulates responsiveness to opioids and antidepressants used for the treatment of chronic pain. We discuss recent data supporting a role of the brain reward pathway in treatment efficacy and we summarize novel findings on intracellular adaptations in the brain reward circuit under chronic pain states.
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In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their therapeutic potential, numerous tools have been developed to study the delta opioid receptor from both a molecular and a functional perspective. ⋯ Here, we describe (1) the cell-based assays used to study the delta opioid receptor. (2) The features of several delta opioid receptor ligands, including peptide and non-peptide drugs. (3) The existing approaches to detect delta opioid receptors in fixed tissue, and debates that surround these techniques. (4) Behavioral assays used to study the in vivo effects of delta opioid receptor agonists; including locomotor stimulation and convulsions that are induced by some ligands, but not others. (5) The characterization of genetically modified mice used specifically to study the delta opioid receptor. Overall, this review aims to provide a guideline for the use of these tools with the final goal of increasing our understanding of delta opioid receptor physiology.
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Major depressive disorder is a serious psychiatric condition associated with high rates of suicide and is a leading cause of health burden worldwide. However, the underlying molecular mechanisms of major depression are still essentially unclear. In our study, a non-targeted gas chromatography-mass spectrometry-based metabolomics approach was used to investigate metabolic changes in the prefrontal cortex of the learned helplessness (LH) rat model of depression. ⋯ Using multivariate and univariate statistical analysis, a total of 18 differential metabolites were identified after the footshock stress protocol. Ingenuity Pathways Analysis and MetaboAnalyst were applied for predicted pathways and biological functions analysis. "Amino Acid Metabolism, Molecule Transport, Small Molecule Biochemistry" was the most significantly altered network in the LH model. Amino acid metabolism, particularly glutamate metabolism, cysteine and methionine metabolism, arginine and proline metabolism, was significantly perturbed in the prefrontal cortex of LH rats.