Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain

AbstractChronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed animals to consume Δ9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Animals stably consumed these gelatins over 3 weeks, with detectable serum levels. We designed a real-time gelatin measurement system, and observed that mice consumed gelatin throughout the light and dark cycles, with THC-gelatin animals consuming less than the other groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after one week while THC or CBD reduced allodynia over three weeks. Hyperalgesia took longer to develop after sciatic nerve injury, but by the last day of testing THC significantly reduced hyperalgesia responses, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by both THC and CBD. This study demonstrates that mice will voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids can provide long-term relief of chronic pain states. Additionally, ultrasonic clicks may objectively represent the pain status of a mouse and could be integrated into future pain models.

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Lack of correlation between spinal microgliosis and long-term development of tactile hypersensitivity in two different sciatic nerve crush injury

Molecular Pain ◽

10.1177/17448069211011326 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110113

Author(s):

Hyoung Woo Kim ◽

Chan Hee Won ◽

Seog Bae Oh

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Sensory Function ◽

Crush Injury ◽

Sciatic Nerve Crush

Microglia activation following peripheral nerve injury has been shown to contribute to central sensitization of the spinal cord for the development of neuropathic pain. In a recent study, we reported that the amount of nerve damage does not necessarily correlate with chronic pain development. Here we compared the response of spinal microglia, using immunohistochemistry as a surrogate of microglial activation, in mice with two different types of crush injury of the sciatic nerve. We confirmed that incomplete crush of the sciatic nerve (partial crush injury, PCI) resulted in tactile hypersensitivity after the recovery of sensory function (15 days after surgery), whereas the hypersensitivity was not observed after the complete crush (full crush injury, FCI). We observed that immunoreactivity for Iba-1, a microglial marker, was greater in the ipsilateral dorsal horn of lumbar (L4) spinal cord of mice 2 days after FCI compared to PCI, positively correlating with the intensity of crush injury. Ipsilateral Iba-1 reactivity was comparable between injuries at 7 days with a significant increase compared to the contralateral side. By day 15 after injury, ipsilateral Iba-1 immunoreactivity was much reduced compared to day 7 and was not different between the groups. Our results suggest that the magnitude of the early microgliosis is dependent on injury severity, but does not necessarily correlate with the long-term development of chronic pain-like hypersensitivity after peripheral nerve injury.

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Benzodiazepines and Pain Management

The Benzodiazepines Crisis ◽

10.1093/med/9780197517277.003.0009 ◽

2020 ◽

pp. 149-159

Author(s):

John F. Peppin ◽

Steven L. Wright

Keyword(s):

Chronic Pain ◽

Sleep Disturbances ◽

Muscle Relaxation ◽

The United States ◽

Term Treatment ◽

Muscle Spasm ◽

The European Union ◽

Long Term Treatment ◽

Few Data

Chronic pain is widespread and the use of opioids for chronic pain is also common. Frequently benzodiazepines are concomitantly prescribed in these patients, for anxiety, sleep disorders, and muscle pain and spasm. In the United States, Canada, and the European Union, increases in benzodiazepine prescribing has been seen, in some cases over 16% over the last decade. Unfortunately, the combination of opioids and benzodiazepines is correlated with overdose and overdose death. Few data exist to support the use of benzos for sleep, muscle spasm, or the long-term treatment of anxiety in the context of pain. It has been further shown that the use of benzodiazepines carries other adverse events and issues. It is estimated that the elimination of benzodiazepines would decrease overdoses by over 15%. The deprescribing of benzodiazepines should become common practice in the professional pain community and their use drastically limited. The authors suggest an approach to the discontinuation of benzodiazepines that includes extensive patient involvement. Other options for anxiety, sleep disturbances, and muscle relaxation are available and should be considered. For those already on these agents (legacy patients), tapering with the goal of discontinuation in a safe and person-centered process should be undertaken.

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Hippocampal Neurogenesis in Conditions of Chronic Stress Induced by Sciatic Nerve Injury in the Rat

Cells Tissues Organs ◽

10.1159/000501236 ◽

2019 ◽

Vol 207 (1) ◽

pp. 58-68 ◽

Cited By ~ 3

Author(s):

Evgeniia Egorova ◽

Anna Starinets ◽

Anna Tyrtyshnaia ◽

Arina Ponomarenko ◽

Igor Manzhulo

Keyword(s):

Chronic Pain ◽

Sciatic Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Sciatic Nerve Injury ◽

Hippocampal Neurogenesis ◽

Chronic Neuropathic Pain ◽

Internal Factors ◽

Macrophage Activity ◽

Primary Location

The dentate gyrus of the hippocampus is the primary location of adult neurogenesis, which is affected by a variety of external and internal factors, including activity of surrounding glial cells. This study concerns alterations in hippocampal neurogenesis and changes in activity of both proinflammatory and neuroprotective microglia/macrophages after sciatic nerve injury in the rat. Here, we demonstrated that the chronic pain induced by a peripheral nerve injury manifests in the hippocampus by a decrease in proliferation (PCNA+) and neurogenesis (DCX+), an increase in proinflammatory cytokines (CD86+), and a reduction in neuroprotective (CD163+) microglia/macrophages. We suggest that a pathological increase microglia/macrophage activity is the cause of neurogenesis suppression observed in chronic neuropathic pain.

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Histomorphometric and ultrastructural evaluation of long term alpha lipoic acid and vitamin b12 use after experimental sciatic nerve injury in rats

Turkish Neurosurgery ◽

10.5137/1019-5149.jtn.13863-14.1 ◽

2015 ◽

Cited By ~ 1

Author(s):

Murat Arikan ◽

Guray Togral ◽

Askin Esen Hasturk ◽

Bahriye Horasanli ◽

Fatma Helvacioglu ◽

...

Keyword(s):

Sciatic Nerve ◽

Vitamin B12 ◽

Nerve Injury ◽

Lipoic Acid ◽

Sciatic Nerve Injury ◽

Alpha Lipoic Acid

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Long-Term Functional Outcome of Penetrating Sciatic Nerve Injury

Journal of Trauma and Acute Care Surgery ◽

10.1097/01.ta.0000245904.54302.a2 ◽

2008 ◽

Vol 64 (3) ◽

pp. 790-795 ◽

Cited By ~ 5

Author(s):

Yoram A. Weil ◽

Andrew D. Pearle ◽

Lampros Palladas ◽

Meir Liebergall ◽

Rami Mosheiff

Keyword(s):

Sciatic Nerve ◽

Functional Outcome ◽

Nerve Injury ◽

Sciatic Nerve Injury

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Micro- and Astroglia Activity in the Spinal Cord Ventrolateral Nucleus Sciatic Nerve Injury in Rats

Cell and Tissue Biology ◽

10.1134/s1990519x20040100 ◽

2020 ◽

Vol 14 (4) ◽

pp. 263-269

Author(s):

A. A. Starinets ◽

E. L. Egorova ◽

A. A. Tyrtyshnaia ◽

I. V. Dyuisen ◽

A. N. Baryshev ◽

...

Keyword(s):

Spinal Cord ◽

Sciatic Nerve ◽

Nerve Injury ◽

Sciatic Nerve Injury ◽

Ventrolateral Nucleus

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Racial and Ethnic Disparities in the Treatment of Chronic Pain

Pain Medicine ◽

10.1093/pm/pnaa427 ◽

2020 ◽

Author(s):

Mary E Morales ◽

R Jason Yong

Keyword(s):

Chronic Pain ◽

Racial Differences ◽

Current Literature ◽

Ethnic Disparities ◽

The United States ◽

Cross Sectional ◽

Effective Interventions ◽

Sociodemographic Profile

Abstract Objective To summarize the current literature on disparities in the treatment of chronic pain. Methods We focused on studies conducted in the United States and published from 2000 and onward. Studies of cross-sectional, longitudinal, and interventional designs were included. Results A review of the current literature revealed that an adverse association between non-White race and treatment of chronic pain is well supported. Studies have also shown that racial differences exist in the long-term monitoring for opioid misuse among patients suffering from chronic pain. In addition, a patient’s sociodemographic profile appears to influence the relationship between chronic pain and quality of life. Results from interventional studies were mixed. Conclusions Disparities exist within the treatment of chronic pain. Currently, it is unclear how to best combat these disparities. Further work is needed to understand why disparities exist and to identify points in patients’ treatment when they are most vulnerable to unequal care. Such work will help guide the development and implementation of effective interventions.

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3D-printed nerve guidance conduits multi-functionalized with canine multipotent mesenchymal stromal cells promote neuroregeneration after sciatic nerve injury in rats

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02315-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Diego Noé Rodríguez-Sánchez ◽

Giovana Boff Araujo Pinto ◽

Luciana Politti Cartarozzi ◽

Alexandre Leite Rodrigues de Oliveira ◽

Ana Livia Carvalho Bovolato ◽

...

Keyword(s):

Growth Factor ◽

Sciatic Nerve ◽

Nerve Injury ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Multipotent Mesenchymal Stromal Cells ◽

Sciatic Nerve Injury ◽

Motor Deficits ◽

3D Printed

Abstract Background Nerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. Combination of nerve guidance conduits (NGCs) with adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) has been performing promising strategy for nerve regeneration. Methods 3D-printed polycaprolactone (PCL)-NGCs were fabricated. Wistar rats subjected to critical sciatic nerve damage (12-mm gap) were divided into sham, autograft, PCL (empty NGC), and PCL + MSCs (NGC multi-functionalized with 106 canine AdMSCs embedded in heterologous fibrin biopolymer) groups. In vitro, the cells were characterized and directly stimulated with interferon-gamma to evaluate their neuroregeneration potential. In vivo, the sciatic and tibial functional indices were evaluated for 12 weeks. Gait analysis and nerve conduction velocity were analyzed after 8 and 12 weeks. Morphometric analysis was performed after 8 and 12 weeks following lesion development. Real-time PCR was performed to evaluate the neurotrophic factors BDNF, GDNF, and HGF, and the cytokine and IL-10. Immunohistochemical analysis for the p75NTR neurotrophic receptor, S100, and neurofilament was performed with the sciatic nerve. Results The inflammatory environment in vitro have increased the expression of neurotrophins BDNF, GDNF, HGF, and IL-10 in canine AdMSCs. Nerve guidance conduits multi-functionalized with canine AdMSCs embedded in HFB improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks. However, the results were not significantly different than those obtained using autografts. These findings were associated with a shift in the regeneration process towards the formation of myelinated fibers. Increased immunostaining of BDNF, GDNF, and growth factor receptor p75NTR was associated with the upregulation of BDNF, GDNF, and HGF in the spinal cord of the PCL + MSCs group. A trend demonstrating higher reactivity of Schwann cells and axonal branching in the sciatic nerve was observed, and canine AdMSCs were engrafted at 30 days following repair. Conclusions 3D-printed NGCs multi-functionalized with canine AdMSCs embedded in heterologous fibrin biopolymer as cell scaffold exerted neuroregenerative effects. Our multimodal approach supports the trophic microenvironment, resulting in a pro-regenerative state after critical sciatic nerve injury in rats.

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