Understanding the Role of Sigma Receptors: What is Sigma Primarily Used For?

October 8, 2025 •

5 min read

First misidentified as a type of opioid receptor in the 1970s, modern pharmacology now recognizes that sigma ($σ$) receptors are a unique class of proteins involved in a wide array of cellular functions. The compelling question, "What is sigma primarily used for?", leads to a diverse list of potential therapeutic applications, including the treatment of neuropsychiatric disorders, neurodegenerative conditions, and chronic pain.

Quick Summary

Sigma receptors are unique protein chaperones involved in modulating calcium, lipids, and neurotransmission. Due to their varied cellular roles, ligands targeting these receptors are being developed for treating conditions from neurodegenerative disorders and neuropathic pain to psychiatric conditions and substance abuse.

Key Points

Chaperone Function: Sigma ($σ$) receptors primarily act as intracellular protein chaperones, helping other proteins fold correctly and modulating various cellular signals.
Diverse Therapeutic Targets: Pharmacological modulation of sigma receptors is being explored for a wide range of conditions, including depression, schizophrenia, chronic pain, and neurodegenerative diseases.
Neuroprotection: Sigma-1 ($σ1$) receptor agonists offer significant neuroprotective benefits by regulating calcium homeostasis, reducing oxidative stress, and mitigating endoplasmic reticulum stress.
Pain Management: Sigma-1 receptor antagonists show promise for treating neuropathic pain and can work synergistically with opioids to enhance analgesia while reducing adverse effects.
Anticancer Potential: Sigma receptors are highly expressed on tumor cells, and agonists or antagonists targeting them have shown antiproliferative properties in preclinical cancer studies.
Substance Abuse Treatment: The interaction of drugs of abuse like cocaine and methamphetamine with sigma receptors makes them potential targets for developing new addiction therapies.

The Diverse Biological Roles of Sigma Receptors

Sigma ($σ$) receptors are a family of unique, ligand-activated membrane proteins found throughout the body, with particularly high concentrations in the central nervous system (CNS). Unlike classical receptors that bind specific neurotransmitters, sigma receptors primarily function as intracellular protein chaperones, helping other proteins fold correctly and influencing a wide variety of cellular signaling pathways. This modulatory, rather than direct, signaling role is central to understanding what sigma is primarily used for in pharmacology.

There are two main subtypes of sigma receptors: sigma-1 ($σ1$) and sigma-2 ($σ2$). The $σ1$ receptor is a well-studied chaperone located at the mitochondrial-associated endoplasmic reticulum membrane (MAM), where it plays a critical role in cellular communication and survival. The identity of the $σ2$ receptor was more recently determined to be the protein TMEM97, and it is also involved in cellular regulation, particularly in proliferating cells.

The unique chaperone function of sigma receptors means that their ligands can modulate a vast network of cellular activities. Agonists and antagonists targeting these receptors can influence ion channel function, intracellular calcium levels, and cholesterol regulation. This broad influence makes them appealing targets for developing new treatments for complex diseases where multiple cellular functions are disrupted.

Applications in Neuropsychiatric and Neurodegenerative Disorders

One of the most promising applications for sigma receptor ligands is in the treatment of various brain disorders. The widespread expression of sigma receptors in the CNS and their influence on neurotransmitter systems, such as dopamine and serotonin, make them ideal targets for new psychiatric drugs.

Depression and Anxiety: Several studies suggest that sigma-1 receptor agonists can produce antidepressant-like effects in animal models, possibly by modulating neurotransmitter release and promoting neuroplasticity. Some existing antidepressants, like fluvoxamine, also have notable affinity for the $σ1$ receptor.
Schizophrenia: Given the complex neurochemical imbalances associated with schizophrenia, sigma receptor ligands are being investigated as potential new antipsychotic medications. The ability of sigma-1 agonists to improve cognitive impairment in preclinical models of schizophrenia is particularly notable.
Cognitive Deficits and Neuroprotection: Sigma receptors play a significant role in neuronal protection against cellular stress, oxidative damage, and inflammation. These neuroprotective effects are being explored for treating conditions like Alzheimer's disease, Parkinson's disease, and Huntington's disease, where neuronal degeneration is a primary feature.

Pain Management

Sigma receptors, particularly the $σ1$ subtype, are deeply implicated in pain signaling and have emerged as a significant target for analgesic development. While they do not directly interact with opioid receptors in the classical sense, $σ1$ receptor antagonists can modulate opioid function and have a significant impact on pain perception.

Neuropathic Pain: Chronic neuropathic pain, which arises from nerve damage, is often difficult to treat. Research shows that $σ1$ receptor antagonists can reduce pain hypersensitivity and alleviate allodynia (pain from normally innocuous stimuli) in animal models.
Opioid-Sparing Effects: The interaction between sigma and opioid systems is complex. Studies indicate that $σ1$ receptor antagonism can potentiate the analgesic effects of opioids, potentially allowing for lower, safer opioid doses while reducing the risk of side effects like tolerance and addiction.

Addiction and Substance Abuse

Many drugs of abuse, including cocaine and methamphetamine, interact with sigma receptors. This suggests that modulating these receptors could be a strategy for treating addiction. Preclinical data show that sigma receptor antagonists can mitigate the reinforcing effects of psychostimulants and block some of their toxic effects.

Cancer Therapeutics

Sigma receptors are also expressed on tumor cells, and this discovery has led to investigations into their role in cancer.

Antiproliferative Effects: Both sigma-1 antagonists and sigma-2 agonists have shown promise in inhibiting tumor cell proliferation in vitro and in vivo. Some researchers are developing sigma ligands as antineoplastic agents, including using radiolabeled ligands for tumor imaging and diagnosis.

Comparison of Sigma Receptor Subtypes

The two main sigma receptor subtypes, $σ1$ and $σ2$, have distinct yet overlapping functions and therapeutic relevance. The following table provides a clear overview of their characteristics.


Feature	Sigma-1 ($σ1$) Receptor	Sigma-2 ($σ2$) Receptor
Molecular Identity	Encoded by the SIGMAR1 gene; acts as a ligand-regulated chaperone protein.	Recently identified as the TMEM97 protein.
Primary Location	Predominantly localized at the MAM, the interface between the endoplasmic reticulum (ER) and mitochondria.	Found in the ER, mitochondria, lysosomes, and plasma membrane, with high expression in proliferating cells.
Key Functions	Modulates intracellular calcium, protein folding, lipid metabolism, oxidative stress response, and ion channel activity.	Involved in cholesterol trafficking, regulation of intracellular calcium, and cell proliferation and survival.
Primary Therapeutic Targets	Neurodegenerative diseases (neuroprotection), psychiatric disorders (antidepressant, antipsychotic), neuropathic pain (analgesia), and substance abuse.	Cancer (antiproliferative effects), neurodegenerative disorders, and potentially pain management.
Ligand Effects	Antagonists and agonists can modulate function and offer therapeutic benefit.	Agonists show antiproliferative effects in cancer models.

The Future of Sigma Receptor Pharmacology

Sigma receptor research continues to evolve rapidly, offering exciting new avenues for drug development. With the resolution of their molecular structures and a deeper understanding of their chaperone function, scientists are better equipped to design highly selective ligands with improved efficacy and fewer side effects. The potential of sigma ligands to act as 'pharmacochaperones'—re-establishing normal cellular function under pathological conditions—is particularly promising.

Moreover, the development of imaging tools, such as positron emission tomography (PET) ligands for visualizing sigma receptors in the human brain, is expected to provide valuable insights into their role in disease progression and the efficacy of new drug candidates. As research progresses, sigma receptors are poised to become critical targets for addressing conditions with significant unmet medical needs, from chronic pain and addiction to devastating neurodegenerative diseases.

For additional scientific context on sigma receptors, you can review publications from the National Institutes of Health. For example, a paper on the potential therapeutic applications of $σ1$ receptor ligands provides a comprehensive overview of preclinical and clinical data: Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands.

Conclusion

In conclusion, while the term "sigma" in pharmacology once held a misleading association with opioid receptors, it is now understood to refer to a unique and versatile family of intracellular proteins. The primary uses for drugs targeting sigma receptors are incredibly diverse, spanning neuropsychiatric disorders like depression and schizophrenia, severe neurological diseases such as Alzheimer's and ALS, and chronic conditions like neuropathic pain. As research reveals more about the distinct roles of the sigma-1 and sigma-2 subtypes, targeted drug development holds immense potential to unlock new therapeutic strategies, moving beyond conventional mechanisms to normalize critical cellular functions that are disrupted in disease states. The future of sigma pharmacology is bright, offering hope for innovative treatments across multiple challenging medical areas.

Frequently Asked Questions

Sigma-1 and sigma-2 are two distinct types of protein receptors. Sigma-1 acts as a ligand-regulated chaperone protein, while sigma-2 has been identified as the protein TMEM97. Both are primarily found intracellularly and play unique roles in regulating cellular function.

No, despite being initially categorized as such in the 1970s, sigma receptors are not a type of opioid receptor. Modern research has clarified they are a unique class of proteins with no structural or evolutionary relation to opioid receptors.

In the brain, sigma receptors are found on neurons and glial cells. They modulate various neurotransmitter systems, including dopamine and serotonin, influence ion channel activity, and are crucial for neuronal survival and neuroprotection against stress and inflammation.

Sigma-1 receptor antagonists can help manage neuropathic pain by reducing hypersensitivity. They can also work alongside opioids, potentially allowing for lower doses and fewer side effects, though they are not conventional opioid analgesics themselves.

Sigma receptors are present on tumor cells, and their modulation can impact cell proliferation. Ligands targeting both sigma-1 and sigma-2 receptors have demonstrated antiproliferative effects in preclinical studies, suggesting potential for novel cancer therapies.

Preclinical studies show that many drugs of abuse, such as cocaine and methamphetamine, interact with sigma receptors. Modulating these receptors with antagonists has been shown to mitigate some of the effects of these substances in animal models, indicating potential for new addiction treatments.

Currently, no selective sigma-receptor drugs are on the market, but several are in development for various conditions, including neurodegenerative disorders and pain. Some existing medications, such as certain antidepressants and antipsychotics, have been found to act on sigma receptors in addition to their primary targets.

Sigma-1 receptors protect against neurodegenerative conditions by modulating intracellular calcium signaling, regulating the ER stress response, and reducing oxidative damage. This helps to preserve and restore neuronal function.