Preclinical Science Regarding Cannabinoids as Analgesics: An Overview

Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics. The present article presents an overview of the preclinical science.

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A Critical Evaluation of Current Concepts in Cerebral Palsy

Physiology ◽

10.1152/physiol.00054.2018 ◽

2019 ◽

Vol 34 (3) ◽

pp. 216-229 ◽

Cited By ~ 9

Author(s):

Joline E. Brandenburg ◽

Matthew J. Fogarty ◽

Gary C. Sieck

Keyword(s):

Risk Factors ◽

Spinal Cord ◽

Cerebral Palsy ◽

Animal Models ◽

Critical Evaluation ◽

Brain Lesions ◽

Spastic Cerebral Palsy ◽

Diagnostic Symptoms ◽

Brain And Spinal Cord ◽

The Brain

Spastic cerebral palsy (CP), despite the name, is not consistently identifiable by specific brain lesions. CP animal models focus on risk factors for development of CP, yet few reproduce the diagnostic symptoms. Animal models of CP must advance beyond risk factors to etiologies, including both the brain and spinal cord.

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Modulation of Glia-Mediated Processes by Spinal Cord Stimulation in Animal Models of Neuropathic Pain

Frontiers in Pain Research ◽

10.3389/fpain.2021.702906 ◽

2021 ◽

Vol 2 ◽

Author(s):

David L. Cedeño ◽

Courtney A. Kelley ◽

Krishnan Chakravarthy ◽

Ricardo Vallejo

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Nervous System ◽

Neuropathic Pain ◽

Animal Models ◽

Glial Cells ◽

Mechanism Of Action ◽

Spinal Cord Stimulation ◽

Expression Levels ◽

Gate Control Theory

Glial cells play an essential role in maintaining the proper functioning of the nervous system. They are more abundant than neurons in most neural tissues and provide metabolic and catabolic regulation, maintaining the homeostatic balance at the synapse. Chronic pain is generated and sustained by the disruption of glia-mediated processes in the central nervous system resulting in unbalanced neuron–glial interactions. Animal models of neuropathic pain have been used to demonstrate that changes in immune and neuroinflammatory processes occur in the course of pain chronification. Spinal cord stimulation (SCS) is an electrical neuromodulation therapy proven safe and effective for treating intractable chronic pain. Traditional SCS therapies were developed based on the gate control theory of pain and rely on stimulating large Aβ neurons to induce paresthesia in the painful dermatome intended to mask nociceptive input carried out by small sensory neurons. A paradigm shift was introduced with SCS treatments that do not require paresthesia to provide effective pain relief. Efforts to understand the mechanism of action of SCS have considered the role of glial cells and the effect of electrical parameters on neuron–glial interactions. Recent work has provided evidence that SCS affects expression levels of glia-related genes and proteins. This inspired the development of a differential target multiplexed programming (DTMP) approach using electrical signals that can rebalance neuroglial interactions by targeting neurons and glial cells differentially. Our group pioneered the utilization of transcriptomic and proteomic analyses to identify the mechanism of action by which SCS works, emphasizing the DTMP approach. This is an account of evidence demonstrating the effect of SCS on glia-mediated processes using neuropathic pain models, emphasizing studies that rely on the evaluation of large sets of genes and proteins. We show that SCS using a DTMP approach strongly affects the expression of neuron and glia-specific transcriptomes while modulating them toward expression levels of healthy animals. The ability of DTMP to modulate key genes and proteins involved in glia-mediated processes affected by pain toward levels found in uninjured animals demonstrates a shift in the neuron–glial environment promoting analgesia.

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Phosphodiesterase 2A Localized in the Spinal Cord Contributes to Inflammatory Pain Processing

Anesthesiology ◽

10.1097/aln.0000000000000270 ◽

2014 ◽

Vol 121 (2) ◽

pp. 372-382 ◽

Cited By ~ 11

Author(s):

Wiebke Kallenborn-Gerhardt ◽

Ruirui Lu ◽

Aaron Bothe ◽

Dominique Thomas ◽

Jessica Schlaudraff ◽

...

Keyword(s):

Spinal Cord ◽

Animal Models ◽

Dorsal Horn ◽

Cyclic Nucleotides ◽

Inflammatory Pain ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Pain Processing

Abstract Background: Phosphodiesterase 2A (PDE2A) is an evolutionarily conserved enzyme that catalyzes the degradation of the cyclic nucleotides, cyclic adenosine monophosphate, and/or cyclic guanosine monophosphate. Recent studies reported the expression of PDE2A in the dorsal horn of the spinal cord, pointing to a potential contribution to the processing of pain. However, the functions of PDE2A in spinal pain processing in vivo remained elusive. Methods: Immunohistochemistry, laser microdissection, and quantitative real-time reverse transcription polymerase chain reaction experiments were performed to characterize the localization and regulation of PDE2A protein and messenger RNA in the mouse spinal cord. Effects of the selective PDE2A inhibitor, BAY 60–7550 (Cayman Chemical, Ann Arbor, MI), in animal models of inflammatory pain (n = 6 to 10), neuropathic pain (n = 5 to 6), and after intrathecal injection of cyclic nucleotides (n = 6 to 8) were examined. Also, cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in spinal cord tissues were measured by liquid chromatography tandem mass spectrometry. Results: The authors here demonstrate that PDE2A is distinctly expressed in neurons of the superficial dorsal horn of the spinal cord, and that its spinal expression is upregulated in response to hind paw inflammation. Administration of the selective PDE2A inhibitor, BAY 60–7550, increased the nociceptive behavior of mice in animal models of inflammatory pain. Moreover, BAY 60–7550 increased the pain hypersensitivity induced by intrathecal delivery of cyclic adenosine monophosphate, but not of cyclic guanosine monophosphate, and it increased the cyclic adenosine monophosphate levels in spinal cord tissues. Conclusion: Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord.

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Acute and Chronic Pain Processing in the Thalamocortical System of Humans and Animal Models

Neuroscience ◽

10.1016/j.neuroscience.2017.09.042 ◽

2018 ◽

Vol 387 ◽

pp. 58-71 ◽

Cited By ~ 19

Author(s):

Alexander Groh ◽

Patrik Krieger ◽

Rebecca A. Mease ◽

Luke Henderson

Keyword(s):

Chronic Pain ◽

Animal Models ◽

Pain Processing ◽

Thalamocortical System

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No brain, no pain

Behavioral and Brain Sciences ◽

10.1017/s0140525x97621494 ◽

1997 ◽

Vol 20 (3) ◽

pp. 486-487

Author(s):

Zsuzsanna Wiesenfeld-Hallin

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Animal Models ◽

Pain Control ◽

Target Article ◽

Limited Usefulness

The theme of my target article was dysfunction of inhibition in the spinal cord as an important factor in the development of chronic pain states. Some commentaries focused on the role of more central mechanisms and the limited usefulness of animal models for understanding mechanisms of human pain. More specific comments concerned the roles of GABA and cholecystokinin in pain control.

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Chronic Pain – What is it?

New Medical Innovations and Research ◽

10.31579/2767-7370/025 ◽

2021 ◽

Vol 2 (5) ◽

pp. 01-02

Author(s):

James David Adams

Keyword(s):

Gene Expression ◽

Chronic Pain ◽

Brain Stem ◽

Pain Processing ◽

Epigenetic Alterations ◽

Pain Sensation ◽

Pain Thresholds ◽

The Brain

The brain stem and brain are involved in chronic pain processing and sensation. This may involve changes in gene expression through epigenetic alterations [1]. Chronic pain is also a learned experience which involves the brain [2]. In chronic pain, thresholds to pain sensation decrease such that pain may be produced by nonpainful stimuli.

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Central Nerve System Impairment, AMA Guides, Sixth Edition: An Overview

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2018.janfeb03 ◽

2018 ◽

Vol 23 (1) ◽

pp. 10-13

Author(s):

James B. Talmage ◽

Jay Blaisdell

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Neurological Impairment ◽

Sixth Edition ◽

Central Nerve System ◽

The Central Nervous System ◽

The One ◽

Nerve System ◽

The Brain

Abstract Injuries that affect the central nervous system (CNS) can be catastrophic because they involve the brain or spinal cord, and determining the underlying clinical cause of impairment is essential in using the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), in part because the AMA Guides addresses neurological impairment in several chapters. Unlike the musculoskeletal chapters, Chapter 13, The Central and Peripheral Nervous System, does not use grades, grade modifiers, and a net adjustment formula; rather the chapter uses an approach that is similar to that in prior editions of the AMA Guides. The following steps can be used to perform a CNS rating: 1) evaluate all four major categories of cerebral impairment, and choose the one that is most severe; 2) rate the single most severe cerebral impairment of the four major categories; 3) rate all other impairments that are due to neurogenic problems; and 4) combine the rating of the single most severe category of cerebral impairment with the ratings of all other impairments. Because some neurological dysfunctions are rated elsewhere in the AMA Guides, Sixth Edition, the evaluator may consult Table 13-1 to verify the appropriate chapter to use.

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