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Pharmacological Modulation of the Sigma 1 Receptor and the Treatment of Pain

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Sigma Receptors: Their Role in Disease and as Therapeutic Targets

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 964))

Abstract

There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy with respect to existing therapies and reduce their unwanted effects. Current preclinical evidence supports the modulatory role of sigma-1 receptors (σ1R) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists on pains of different etiologies. σ1R is highly expressed in different pain areas of the CNS and the periphery (particularly dorsal root ganglia), and interacts and modulates the functionality of different receptors and ion channels . The antagonism of σ1R leads to decreased amplification of pain signaling within the spinal cord (central sensitization), but recent data also support a role at the periphery. σ1R antagonists have consistently demonstrated efficacy in neuropathic pain , but also in other types of pain including inflammatory, orofacial, visceral, and post-operative pain. Apart from acting alone, when combined with opioids, σ1R antagonists enhance opioid analgesia but not opioid-induced unwanted effects. Interestingly, unlike opioids, σ1R antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitive effects in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. Accordingly, σ1R antagonists are not strictly analgesics; they are antiallodynic and antihyperalgesic drugs acting when the system is sensitized following prolonged noxious stimulation or persistent abnormal afferent input (e.g., secondary to nerve injury). These are distinctive features allowing σ1R antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain .

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Declaration of Interest

The authors are full-time employees of ESTEVE. The authors have no other relevant affiliation or financial involvement, have received no payment in preparation of this manuscript or have any conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Authors and Affiliations

  1. Drug Discovery and Preclinical Development, ESTEVE. Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028, Barcelona, Spain

    Manuel Merlos, Javier Burgueño, Enrique Portillo-Salido, Carlos Ramón Plata-Salamán & José Miguel Vela

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  1. Manuel Merlos
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  2. Javier Burgueño
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  3. Enrique Portillo-Salido
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  4. Carlos Ramón Plata-Salamán
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  5. José Miguel Vela
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Correspondence to José Miguel Vela .

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Editors and Affiliations

  1. Departments of Cellular Biology and Anatomy and Ophthalmology and the James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

    Sylvia B. Smith

  2. Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland, USA

    Tsung-Ping Su

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Merlos, M., Burgueño, J., Portillo-Salido, E., Plata-Salamán, C.R., Vela, J.M. (2017). Pharmacological Modulation of the Sigma 1 Receptor and the Treatment of Pain. In: Smith, S., Su, TP. (eds) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. Advances in Experimental Medicine and Biology, vol 964. Springer, Cham. https://doi.org/10.1007/978-3-319-50174-1_8

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