Sigma-1 receptors and animal studies centered on pain and analgesia

Abstract

Introduction: Neuropathic pain is difficult to relieve with standard analgesics and tends to be resistant to opioid therapy. Sigma-1 receptors activated during neuropathic injury may sustain pain. Neuropathic injury activates sigma-1 receptors, which results in activation of various kinases, modulates the activity of multiple ion channels, ligand activated ion channels and voltage-gated ion channels; alters monoamine neurotransmission and dampens opioid receptors G-protein activation. Activation of sigma-1 receptors tonically inhibits opioid receptor G-protein activation and thus dampens analgesic responses. Therefore, sigma-1 receptor antagonists are potential analgesics for neuropathic and adjuvants to opioid therapy.

Areas covered: This article reviews the importance of sigma-1 receptors as pain generators in multiple animal models in order to illustrate both the importance of these unique receptors in pathologic pain and the potential benefits to sigma-1 receptor antagonists as analgesics.

Expert opinion: Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression).

Keywords:

• agonist
• analgesia
• antagonist
• pain
• receptor
• sigma

Acknowledgments

The author thanks G Pasternak for critically reviewing the manuscript and A Mendelsohn for the medical illustrations.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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