The Sigma Enigma: A Narrative Review of Sigma Receptors

Pergolizzi, Joseph V.; Varrassi, Giustino; Coleman, Mark; Breve, Frank; Christo, Dana K.; Christo, Paul J.; Moussa, Charbel

doi:10.7759/cureus.35756

Cited by 13 publications

(22 citation statements)

References 113 publications

(168 reference statements)

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“…They are distributed in the CNS and in several peripheral tissues, and they are also overexpressed in many kinds of tumor cells. The specific functional roles of the two subtypes have been progressively defined, acquiring clinical relevance [ 37 , 38 ]. By themselves, or in concerted mechanisms involving other receptors, sigma receptors participate in motor function, regulation of smooth muscle contraction, neurotransmitter synthesis and release, opioid analgesia modulation, neuro-degeneration and cognitive impairment, immune homeostasis, and sterol biosynthesis.…”

Section: Affinity To Sigma Receptorsmentioning

confidence: 99%

3,3-Disubstituted 3,4-Dihydro-1,2,4-benzotriazines: Chemistry, Biological Activity, and Affinity to Sigma Receptors

Sparatore,

Sparatore

2023

Molecules

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By reducing the 2-nitrophenylhydrazone of cyclohexanone with sodium dithionite, an unexpected yellow compound was obtained instead of the corresponding colorless amino derivative. Many years later, the structure of this compound, namely, cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, was demonstrated. From that time, the reduction of 2-nitrophenylhydrazones of different kinds of ketones, followed by air oxidation of the initially formed amino compounds, has represented a general way to synthesize a variety of 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines. Many derivatives have been obtained so far by a single research group, and most of them have demonstrated interesting pharmacological activities, mainly antihypertensive, anti-inflammatory, and diuretic effects and other activities with lower diffusion. Moreover, 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines represent a novel class of ligands for sigma receptors, with nanomolar affinity to the σ1 subtype. This property might promote the development of agents for cardiovascular, neurodegenerative, and proliferative pathologies. The present commentary, by collecting compounds and biological results obtained so far, intends to celebrate the centennial of the discovery of the first member of this class of compounds and to promote further investigation in the field.

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Section: Affinity To Sigma Receptorsmentioning

confidence: 99%

3,3-Disubstituted 3,4-Dihydro-1,2,4-benzotriazines: Chemistry, Biological Activity, and Affinity to Sigma Receptors

Sparatore,

Sparatore

2023

Molecules

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“…Nerve blocks and device-based pain therapy may be helpful in treating certain types of neuropathic pain, but there are only a few studies to help guide clinical decision-making [ 59 ]. New drug targets may result in new agents for neuropathic pain control, such as the sigma receptors [ 60 ].…”

Section: Reviewmentioning

confidence: 99%

What’s New in Neuropathy?

Varrassi,

Tamburin,

Zis

et al. 2023

Cureus

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Neuropathic pain presents diagnostic and treatment challenges. Despite recent advances in our understanding of the diagnosis and treatment of neuropathy, much remains to be elucidated. Familiar with neuropathy is the paradox that aberrant nerve signaling causes both sensory loss and pain. Voltage-gated sodium channels play an important role in neuronal electrogenesis and communication among neurons, and their dysregulation leads to hyperexcitability and pain. While numerous validated diagnostic assessment tools are available for neuropathy, patients often experience a diagnostic delay about the cause of their neuropathy. New research is defining more specific types of neuropathy beyond peripheral and central forms. The prevalence of pain varies by type of neuropathy, with chronic idiopathic axonal polyneuropathy associated with the highest proportion of patients experiencing pain. In the majority of types, it exceeds 50%. Gluten neuropathy, a form of peripheral neuropathy, is a new diagnostic consideration. It may require electrochemical conductance testing of hands and feet to test for sudomotor dysfunction. Among those with serologically confirmed gluten sensitivity or celiac disease, gluten neuropathy is a common neurological manifestation and may be addressed at least partially by a gluten-free diet. In Greece, a new neuropathic pain registry was created in 2014 in order to help gather data from real-world neuropathic pain patients. While still in its earliest phase, this registry has already produced demographic and treatment data that suggest suboptimal prescribing and less than recommended use of interventional procedures. Awareness campaigns are underway to encourage more Greek pain clinics to participate in this important registry.

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“…The role of genetics, the microbiome, and other factors may be the next radical paradigm shift in pain medicine [ 91 ]. New therapeutic targets are being discovered [ 92 ]. There are many exciting new horizons in pain care, as well as revitalization efforts for the mainstays of pain care.…”

Section: Reviewmentioning

confidence: 99%

Looking Back, Moving Forward in Pain Medicine

Paladini,

Gharibo,

Khalbous

et al. 2023

Cureus

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Pain is an ancient medical complaint and a clinical riddle that has never been entirely solved. Looking back into history was the springboard to a look into the future of pain medicine. This article was based on a series of presentations given in a recent congress (May 2023) and represents the research, views, and opinions of the authors. Opium has been used for millennia to treat pain, but when it gained broad use in the United States in the 1980s and 1990s, it was so vastly overprescribed and mis-prescribed that it led to a public health crisis. This, in turn, led to the reaction where opioids at times were under-prescribed, leaving out many patients who may have benefited from opioids while leaving many legacy pain patients to manage withdrawal on their own and with few analgesic options. Cannabinoids (CB) were likewise widely used for various conditions, including pain, but were outlawed in the 20th century, only to be brought back as a potential analgesic agent. Interventional pain medicine is a developing discipline and has reinforced the concept of the interdisciplinary pain clinic. It plays an increasingly important part in modern medicine overall, especially with the support of ultrasound, for both diagnosis and therapy. Today, the views about pain have changed. Anyone has accepted that pain is not purely a physical phenomenon but a biopsychosocial phenomenon that occurs within a cultural context. Pain management remains a small but vitally important medical subspecialty that is critical from a functional enablement and population health perspective, which is helping to navigate new therapeutic targets, new drugs and routes of administration, greater understanding of pain psychology, and new technologies. Pain control today means early intervention, functional enablement through pain alleviation, educating patients about pain management, and minimizing the transition from acute to chronic pain.

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The Sigma Enigma: A Narrative Review of Sigma Receptors

Cited by 13 publications

References 113 publications

3,3-Disubstituted 3,4-Dihydro-1,2,4-benzotriazines: Chemistry, Biological Activity, and Affinity to Sigma Receptors

3,3-Disubstituted 3,4-Dihydro-1,2,4-benzotriazines: Chemistry, Biological Activity, and Affinity to Sigma Receptors

What’s New in Neuropathy?

Looking Back, Moving Forward in Pain Medicine

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