Sphingosine-1-phosphate Receptor Subtype 1 Antagonists may be the Unmet Medical Need for Morphine-induced Hyperalgesia and Antinociceptive Tolerance

2021 ◽  
Author(s):  
Y. Brik
Keyword(s):  
Chronic Pain ◽  
Adverse Effects ◽  
Receptor Subtype ◽  
Ongoing Research ◽  
Medical Need ◽  
Sphingosine 1 Phosphate ◽  
Opioid Induced Hyperalgesia ◽  
The Central Nervous System ◽  
Antinociceptive Tolerance ◽  
New Treatments

Opioids such as morphine are frequently used for chronic pain management despite their many adverse effects. Ongoing research aims at either finding new treatments to replace opioids or reducing its heavy adverse effects due to long-term use: opioid-induced hyperalgesia and antinociceptive tolerance. In a recent study, Doyle et al. (2020) demonstrate that the activation of sphingosine-1-phosphate receptor subtype 1 (S1PR1) in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in a rodent model of chronic pain. By targeting S1PR1 with molecules with functional antagonistic properties (some of which are FDA-approved for multiple sclerosis treatment), hyperalgesia and tolerance were significantly reduced without modifying morphine pharmacokinetics or efficacy.

scholarly journals Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain

2019 ◽  
Vol 116 (21) ◽  
pp. 10557-10562 ◽  
Author(s):  
Zhoumou Chen ◽  
Timothy M. Doyle ◽  
Livio Luongo ◽  
Tally M. Largent-Milnes ◽  
Luigino Antonio Giancotti ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Molecular Mechanisms ◽  
Interleukin 10 ◽  
Sphingolipid Metabolism ◽  
Receptor Subtype ◽  
Endogenous Opioid ◽  
Major Health Problem ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

scholarly journals Ketamine Use for Cancer and Chronic Pain Management

2021 ◽  
Vol 11 ◽  
Author(s):  
Clayton Culp ◽  
Hee Kee Kim ◽  
Salahadin Abdi
Keyword(s):  
Chronic Pain ◽  
Adverse Event ◽  
Case Reports ◽  
Aspartate Receptor ◽  
Opioid Induced Hyperalgesia ◽  
Central Nervous System Sensitization ◽  
The Central Nervous System ◽  
Resistant Depression ◽  
Human Use ◽  
Chronic Pain Conditions

Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. Due to an undesirable adverse event profile when used as an anesthetic it had widely fallen out of human use in favor of more modern agents. However, it has recently been explored for several other indications such as treatment resistant depression and chronic pain. Several recent studies and case reports compiled here show that ketamine is an effective analgesic in chronic pain conditions including cancer-related neuropathic pain. Of special interest is ketamine’s opioid sparing ability by counteracting the central nervous system sensitization seen in opioid induced hyperalgesia. Furthermore, at the sub-anesthetic concentrations used for analgesia ketamine’s safety and adverse event profiles are much improved. In this article, we review both the basic science and clinical evidence regarding ketamine’s utility in chronic pain conditions as well as potential adverse events.

scholarly journals Opioid Induced Hyperalgesia, a Research Phenomenon or a Clinical Reality? Results of a Canadian Survey

2020 ◽  
Vol 10 (2) ◽  
pp. 27
Author(s):  
Grisell Vargas-Schaffer ◽  
Suzie Paquet ◽  
Andrée Neron ◽  
Jennifer Cogan
Keyword(s):  
Chronic Pain ◽  
Nmda Antagonist ◽  
Treatment Modalities ◽  
Clinical Test ◽  
Physician Practice ◽  
Clinical Tests ◽  
Opioid Rotation ◽  
Number Of Patients ◽  
Opioid Induced Hyperalgesia ◽  
Age Range

Background: Very little is known regarding the prevalence of opioid induced hyperalgesia (OIH) in day to day medical practice. The aim of this study was to evaluate the physician’s perception of the prevalence of OIH within their practice, and to assess the level of physician’s knowledge with respect to the identification and treatment of this problem. Methods: An electronic questionnaire was distributed to physicians who work in anesthesiology, chronic pain, and/or palliative care in Canada. Results: Of the 462 responses received, most were from male (69%) anesthesiologists (89.6%), in the age range of 36 to 64 years old (79.8%). In this study, the suspected prevalence of OIH using the average number of patients treated per year with opioids was 0.002% per patient per physician practice year for acute pain, and 0.01% per patient per physician practice year for chronic pain. Most physicians (70.2%) did not use clinical tests to help make a diagnosis of OIH. The treatment modalities most frequently used were the addition of an NMDA antagonist, combined with lowering the opioid doses and using opioid rotation. Conclusions: The perceived prevalence of OIH in clinical practice is a relatively rare phenomenon. Furthermore, more than half of physicians did not use a clinical test to confirm the diagnosis of OIH. The two main treatment modalities used were NMDA antagonists and opioid rotation. The criteria for the diagnosis of OIH still need to be accurately defined.

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

2016 ◽  
Vol 473 (18) ◽  
pp. 2717-2736 ◽  
Author(s):  
Christoforos Tsantoulas ◽  
Elizabeth R. Mooney ◽  
Peter A. McNaughton
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Ion Channels ◽  
Warning Signal ◽  
Sensory Nerves ◽  
Nociceptive Neurons ◽  
Pain Syndromes ◽  
Medical Need ◽  
Pathological Pain ◽  
Genetic Deletion

Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

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