Neuroscience
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A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. ⋯ Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy? This review will use the experts' answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.
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In addition to being a key component of the autonomic nervous system, acetylcholine acts as a prominent neurotransmitter and neuromodulator upon release from key groups of cholinergic projection neurons and interneurons distributed across the central nervous system. It has been more than forty years since it was discovered that cholinergic transmission profoundly modifies the perception of pain. Directly activating cholinergic receptors or extending the action of endogenous acetylcholine via pharmacological blockade of acetylcholine esterase reduces pain in rodents as well as humans; conversely, inhibition of muscarinic cholinergic receptors induces nociceptive hypersensitivity. ⋯ Moreover, we attempt to provide an overview of how some of the salient regions in the pain network spanning the brain, such as the primary somatosensory cortex, insular cortex, anterior cingulate cortex, the medial prefrontal cortex and descending modulatory systems are influenced by cholinergic modulation. Finally, we critically discuss the clinical relevance of cholinergic signaling to pain therapy. Cholinergic mechanisms contribute to several both conventional as well as unorthodox forms of pain treatments, and reciprocal interactions between cholinergic and opioidergic modulation impact on the function and efficacy of both opioids and cholinomimetic drugs.
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Chronic pain is a serious condition that significantly impairs the quality of life, affecting an estimate of 1.5 billion people worldwide. Despite the physiological, emotional and financial burden of chronic pain, there is still a lack of efficient treatments. ⋯ Intrathecal administration of NPY in animal models of neuropathic, inflammatory or postoperative pain has been shown to cause analgesia, even though its exact mechanisms are still unclear. It remains to be seen whether these promising central antinociceptive effects of NPY can be transferred into a future treatment for chronic pain.
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The transmission of noxious stimuli from peripheral receptors to the cortex involves multiple central ascending pathways. While projections to areas in the brainstem and diencephalon are likely involved in mediating the immediate behavioral responses to pain, the assessment of the sensory and emotional/motivational components of pain are likely processed in parallel ascending pathways that relay in the thalamus on their way to the cerebral cortex. ⋯ In addition, we outline experimental animal and human evidence of functional, anatomical and biochemical alterations in thalamocortical circuits that may be responsible for altered thalamocortical rhythms and the persistent presence of pain following nervous system damage. Finally, we discuss advances in clinical and preclinical development of chronic pain treatments aimed at altering neural and glial function.
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Secondary mechanical hyperalgesia to punctate mechanical stimuli and light touch (allodynia) are prominent symptoms in neuropathic pain states. In a combined microneurographic and psychophysical study, we investigated the role of mechano-insensitive (silent) nociceptors regarding induction. Electrical thresholds of mechano-sensitive and silent nociceptors were assessed by microneurography with two closely spaced intracutaneous electrodes (i.c.) and a transcutaneous configuration (t.c.) in the foot dorsum. ⋯ Punctate hyperalgesia was evoked at very low stimulation frequencies of 1/20 Hz (7/7 subjects), whereas the induction of an axon reflex flare required stimulation at 1/5 Hz. Electrical stimulation which is sufficient to excite mechano-insensitive C nociceptors can induce secondary mechanical hyperalgesia even at low frequencies supporting a role of such low-level input to clinical pain states. Thus, differential nociceptor class-specific input to the spinal cord adds to the complexity of modulatory mechanisms that determine nociceptive processing in the spinal cord.