Developing Modern Pain Therapies

Manion, John; Waller, Matthew A.; Clark, Teleri; Massingham, Joshua N.; Neely, G. Gregory

doi:10.3389/fnins.2019.01370

Cited by 32 publications

(18 citation statements)

References 232 publications

(248 reference statements)

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“…Chronic neuropathic pain is an exacerbated or prolonged pain caused by damage or disease affecting the somatosensory nervous system (including nerve injury, cancer, diabetes or viral infection). Chronic neuropathic pain can be classified as a neurodegenerative disease [ 83 , 84 ] that culminates in decreased central inhibition in the spinal cord [ 85 , 86 , 87 ].…”

Section: Main Textmentioning

confidence: 99%

Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges

Ford

Pearlman

Ruan

et al. 2020

Cells

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Neurodegenerative diseases are characterized by irreversible cell damage, loss of neuronal cells and limited regeneration potential of the adult nervous system. Pluripotent stem cells are capable of differentiating into the multitude of cell types that compose the central and peripheral nervous systems and so have become the major focus of cell replacement therapies for the treatment of neurological disorders. Human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC)-derived cells have both been extensively studied as cell therapies in a wide range of neurodegenerative disease models in rodents and non-human primates, including Parkinson’s disease, stroke, epilepsy, spinal cord injury, Alzheimer’s disease, multiple sclerosis and pain. In this review, we discuss the latest progress made with stem cell therapies targeting these pathologies. We also evaluate the challenges in clinical application of human pluripotent stem cell (hPSC)-based therapies including risk of oncogenesis and tumor formation, immune rejection and difficulty in regeneration of the heterogeneous cell types composing the central nervous system.

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Section: Main Textmentioning

confidence: 99%

Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges

Ford

Pearlman

Ruan

et al. 2020

Cells

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“…Chronic pain is the most common complaint of patients in outpatient clinics (Upshur et al, 2006), and effective therapies remain limited (Meyer-Rosberg et al, 2001;Dworkin et al, 2013;Finnerup et al, 2015). More importantly, these therapies lack specificity to the underlying pathophysiology and carry a high burden of side effects for pain patients (Manion et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

An Amygdalo-Parabrachial Pathway Regulates Pain Perception and Chronic Pain

et al. 2020

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The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to lateral parabrachial (LPB) neurons from the CeA in animals of either sex. Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges, responses that far outlast the stimulus, compared with controls. LPB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that, in both rats and mice, LPB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin, and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naive animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.

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“…Acute pain is considered an alarm system for protecting body integrity, while chronic pain may serve an adaptative role ( Crook et al., 2014 ; Lister et al., 2020 ). In spite of its role, chronic pain is a major health problem around the world with a prevalence up to 50% ( Fayaz et al., 2016 ; Manion et al., 2019 ). Chronic pain (defined in humans as the pain of more than three months) describes pain such as neuropathic pain, low-back pain, osteoarthritis, traumatic injury and postoperative pain, among others.…”

Section: Introductionmentioning

confidence: 99%

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

et al. 2020

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Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/ calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

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Developing Modern Pain Therapies

Cited by 32 publications

References 232 publications

Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges

Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges

An Amygdalo-Parabrachial Pathway Regulates Pain Perception and Chronic Pain

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

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