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Proceedings of the National Academy of... Aug 2023Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small...
Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked Na1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to Na1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the Na1.7 CRS over other Na isoforms. Substitution of the Na1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased Na1.7 currents. A cell-penetrant decoy peptide corresponding to the Na1.7-CRS reduced Na1.7 currents and trafficking, decreased presynaptic Na1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the Na1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a Na1.7 -targeted gene therapy, we packaged a plasmid encoding the Na1.7-CRS in an AAV virus. Treatment with this virus reduced Na1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy. These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain.
Topics: Animals; Hyperalgesia; Chronic Pain; Macaca mulatta; Neuralgia; NAV1.7 Voltage-Gated Sodium Channel; Ganglia, Spinal; NAV1.8 Voltage-Gated Sodium Channel
PubMed: 37498871
DOI: 10.1073/pnas.2217800120 -
Neuron Nov 2023Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility...
Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca and peroxisome proliferator-activated receptor α (PPAR⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.
Topics: Rats; Animals; Humans; Analgesics, Opioid; Chronic Pain; Acetylcholine; Rats, Sprague-Dawley; Pain Measurement; Drug Tolerance; Periaqueductal Gray; Cholinergic Agents; Receptors, Nicotinic
PubMed: 37734381
DOI: 10.1016/j.neuron.2023.08.017 -
Nature Communications Jun 2023Musculoskeletal chronic pain is prevalent in individuals with Alzheimer's disease (AD); however, it remains largely untreated in these patients, raising the possibility...
Musculoskeletal chronic pain is prevalent in individuals with Alzheimer's disease (AD); however, it remains largely untreated in these patients, raising the possibility that pain mechanisms are perturbed. Here, we utilise the TASTPM transgenic mouse model of AD with the K/BxN serum transfer model of inflammatory arthritis. We show that in male and female WT mice, inflammatory allodynia is associated with a distinct spinal cord microglial response characterised by TLR4-driven transcriptional profile and upregulation of P2Y12. Dorsal horn nociceptive afferent terminals release the TLR4 ligand galectin-3 (Gal-3), and intrathecal injection of a Gal-3 inhibitor attenuates allodynia. In contrast, TASTPM mice show reduced inflammatory allodynia, which is not affected by the Gal-3 inhibitor and correlates with the emergence of a P2Y12 TLR4 microglia subset in the dorsal horn. We suggest that sensory neuron-derived Gal-3 promotes allodynia through the TLR4-regulated release of pro-nociceptive mediators by microglia, a process that is defective in TASTPM due to the absence of TLR4 in a microglia subset.
Topics: Mice; Male; Female; Animals; Hyperalgesia; Microglia; Alzheimer Disease; Galectin 3; Nociception; Toll-Like Receptor 4; Spinal Cord; Spinal Cord Dorsal Horn; Mice, Transgenic; Chronic Pain; Disease Models, Animal
PubMed: 37349313
DOI: 10.1038/s41467-023-39077-1 -
Cephalalgia : An International Journal... Apr 2024Many risk factors have been associated with migraine progression, including insufficient and ineffective utilization of migraine medications; however, they have been... (Review)
Review
BACKGROUND
Many risk factors have been associated with migraine progression, including insufficient and ineffective utilization of migraine medications; however, they have been inadequately explored. This has resulted in suboptimal usage of medications without effective altering of prescribing recommendations for patients, posing a risk for migraine chronification.
METHODS
Our aim is to conduct a comprehensive review of the available evidence regarding the underuse of migraine medications, both acute and preventive. The term "underuse" includes, but is not limited to: (1) ineffective use of appropriate and inappropriate medication; (2) underutilization; (3) inappropriate timing of usage; and (4) patient dissatisfaction with medication.
RESULTS
The underuse of both acute and preventive medications has been shown to contribute to the progression of migraine. In terms of acute medication, chronification occurs as a result of insufficient drug use, including failure of the prescriber to select the appropriate type based on pain intensity and disability, patients taking medication too late (more than 60 minutes after the onset or after central sensitization has occurred as evidenced by allodynia), and discontinuation because of lack of effect or intolerable side effects. The underlying cause of inadequate effectiveness of acute medication lies in its inability to halt the propagation of peripheral activation to central sensitization in a timely manner. For oral and injectable preventive migraine medications, insufficient efficacy and intolerable side effects have led to poor adherence and discontinuation with subsequent progression of migraine. The underlying pathophysiology here is rooted in the repetitive stimulation of afferent sensory pain fibers, followed by ascending brainstem pain pathways plus dysfunction of the endogenous descending brainstem pain inhibitory pathway. Although anti-calcitonin gene-related peptide (CGRP) medications partially address pain caused by the above factors, including decreased efficacy and tolerability from conventional therapy, some patients do not respond well to this treatment. Research suggests that initiating preventive anti-CGRP treatment at an early stage (during low frequency episodic migraine attacks) is more beneficial than commencing it during high frequency episodic attacks or when chronic migraine has begun.
CONCLUSIONS
The term "medication underuse" is underrecognized, but it holds significant importance. Optimal usage of acute care and preventive migraine medications could potentially prevent migraine chronification and improve the treatment of migraine attacks.
Topics: Humans; Headache; Migraine Disorders; Pain; Risk Factors; Brain Stem; Calcitonin Gene-Related Peptide
PubMed: 38613233
DOI: 10.1177/03331024241245658