Pain
-
Peripheral neuropathy is the most common neurodegenerative disease affecting hundreds of millions of patients worldwide and is an important cause of chronic pain. Typical peripheral neuropathies are characterized by dysesthesias including numbness, crawling skin, a sensation of "pins and needles," and burning and stabbing pain. In addition, peripheral neuropathy can affect the motor and autonomic systems leading to symptoms such as weakness, constipation, and dysregulation of blood pressure. ⋯ Many neuropathies are due to degeneration of long axons; however, the mechanisms driving axon loss were unknown, and so no therapies are available to preserve vulnerable axons and prevent the development of peripheral neuropathy. With the recent identification of SARM1 as an injury-activated NADase enzyme that triggers axon degeneration, there is now a coherent picture emerging for the mechanism of axonal self-destruction. Here, we will present evidence that inhibiting the SARM1 pathway can prevent the development of peripheral neuropathy, describe the emerging mechanistic understanding of the axon degeneration program, and discuss how these mechanistic insights may be translated to the clinic for the prevention and treatment of peripheral neuropathy and other neurodegenerative disorders.
-
This review expounds on types and properties of biomarkers for chronic pain, given a mechanistic model of processes underlying development of chronic pain. It covers advances in the field of developing biomarkers for chronic pain, while outlining the general principles of categorizing types of biomarkers driven by specific hypotheses regarding underlying mechanisms. Within this theoretical construct, example biomarkers are described and their properties expounded. We conclude that the field is advancing in important directions and the developed biomarkers have the potential of impacting both the science and the clinical practice regarding chronic pain.
-
Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. ⋯ Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.
-
The nucleus accumbens (NAc) has been implicated in sleep, reward, and pain modulation, but the relationship between these functional roles is unclear. This study aimed to determine whether NAc function at the onset and offset of a noxious thermal stimulus is enhanced by rewarding music, and whether that effect is reversed by experimental sleep disruption. Twenty-one healthy subjects underwent functional magnetic resonance imaging scans on 2 separate days after both uninterrupted sleep and experimental sleep disruption. ⋯ Sleep disruption increased reward-related connectivity between the NAc and the anterior midcingulate cortex at pain onset. This study thus indicates that experimental sleep disruption modulates NAc function during the onset of pain in a manner that may be conditional on the presence of competing reward-related stimuli. These findings point to potential mechanisms for the interaction between sleep, reward, and pain, and suggest that sleep disruption affects both the detection and processing of aversive stimuli that may have important implications for chronic pain.
-
Chronic pain is associated with brain atrophy with limited evidence on its impact in the older adult's brain. We aimed to determine the associations between chronic pain and a brain aging biomarker in persons aged 60 to 83 years old. Participants of the Neuromodulatory Examination of Pain and Mobility Across the Lifespan (NEPAL) study (N = 47) completed demographic, psychological, and pain assessments followed by a quantitative sensory testing battery and a T1-weighted magnetic resonance imaging. ⋯ An "older" brain was significantly associated with decreased vibratory (r = 0.323; P = 0.033) and thermal (r = 0.345; P = 0.023) detection, deficient endogenous pain inhibition (F[1,25] = 4.6; P = 0.044), lower positive affect (r = -0.474; P = 0.005), a less agreeable (r = -0.439; P = 0.020), and less emotionally stable personality (r = -0.387; P = 0.042). Our findings suggest that chronic pain is associated with added "age-like" brain atrophy in relatively healthy, community-dwelling older individuals, and future studies are needed to determine the directionality of our findings. A brain aging biomarker may help identify people with chronic pain at a greater risk of functional decline and poorer health outcomes.