Pain
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Diabetes mellitus (DM) is a major global health concern, affecting more than 9% of the world population. The most common complication of DM is diabetic peripheral neuropathy (DPN), which leads to neuropathic pain in as many as 50% of patients. Despite its prevalence, there is neither good prevention of nor treatments for DPN, representing a major gap in care for the many who are afflicted. ⋯ It then discusses structural changes in Aβ, Aδ, and C fibers throughout the progression of DPN and their respective contributions to painful DPN in both human patients and DM mouse models. Finally, it highlights remaining questions on sensory neuron structure-function relationships in painful DPN and how we may address these in mouse models by using technological advances in cell-specific modulation. Only when these structure-function relationships are understood, can novel targeted therapeutics be developed for DPN.
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The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. ⋯ This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward.
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Small families carrying rare mutations, which I call "pointer-kindreds," can teach us important lessons. Here, I provide some examples from the field of pain.
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Quantitative sensory testing (QST) is a formal variant of a time-honoured clinical examination technique in neurology, the sensory examination. Prototypical QST profiles have been found in human surrogate models of peripheral sensitization, central sensitization, and deafferentation. Probabilistic sorting of individual patients to any combination of these profiles has been developed, and there is emerging evidence for the predictive value of such sensory profiles for treatment efficacy. ⋯ Several psychological factors had previously been found to be predictors of pain chronicity (catastrophizing, self-efficacy, and neuroticism). The relative importance of psychological vs sensory testing predictors has not been evaluated. It is likely that both will have differential roles in clinical practice.
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Neuropathic itch is clinically important but has received much less attention as compared to neuropathic pain. In the past decade, itch-specific pathways have been characterized on a cellular and molecular level, but their exact role in the pathophysiology of neuropathic itch is still unclear. Traditionally, mutually exclusive theories for itch such as labeled line, temporal/spatial pattern, or intensity theory have been proposed, and experimental studies in mice mainly favor the specificity theory of itch. ⋯ Rarefication of skin innervation in neuropathy could provide a "spatial contrast" discharge pattern, and axotomy could induce de novo expression of the itch-specific spinal neuropeptide, gastrin-releasing peptide, in primary afferent nociceptors, thereby modulating itch processing in the dorsal horn. Thus, clinical neuropathy may generate itch by changes in the spatial and temporal discharge patterns of nociceptors, hijacking the labeled line processing of itch and abandoning the canonical scheme of mutual exclusive itch theories. Moreover, the overlap between itch and pain symptoms in neuropathy patients complicates direct translation from animal experiments and, on a clinical level, necessitates collaboration between medical specialities, such as dermatologists, anesthesiologists, and neurologists.