The Emerging Role of Sigma Receptors in Pain Medicine

Self Cite

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.

Section: Discussionmentioning

confidence: 99%

Looking Back, Moving Forward in Pain Medicine

Paladini,

Gharibo,

Khalbous

et al. 2023

Self Cite

“…This property aids in the proper transport and folding of proteins, a property that is required for proper functioning. Such an activity would have broad therapeutic utility in situations of dysregulated or disrupted physiological pathways or excursions from baseline activity, such as is hypothesized to occur in neuropathic pain [2,3]. Here, we review some recent publications that provide examples of the analgesic activity of some S2Rselective compounds.…”

Section: Introductionmentioning

confidence: 99%

Recent Developments in Sigma-2 Receptor Compounds for Pain

Raffa,

Pergolizzi

2024

After years of enigmatic pharmacology, non-selective ligands, and uncertain clinical application, sigma receptors have emerged as interesting therapeutic drug discovery-development targets. Two subtypes of sigma receptors have now been cloned, sigma-1 receptor (S1R) and sigma-2 receptor (S2R), and there has been much complementary and converging information from advances in molecular biology, computer modeling, virtual screening, and in vitro and in vivo testing. One of several evolving areas of therapeutic potential is for the treatment of pain. In particular, there is accumulating recent evidence from preclinical models that the demonstrated positive effects of S2R compounds in these models suggest possible positive implications for clinical effectiveness against pains that have a neuropathic component. Such pain conditions have imperfect therapeutic options currently. The addition of new drugs to the now available armamentarium would represent a very significant advance for the large number of patients who suffer from these types of intractable pain. Further research is needed to identify and characterize compounds that have not only good in vitro activity but also the characteristics needed to enter clinical trials. Here, we summarize some of the recent reports of the analgesic activity of S2R compounds.

“…As described in recent reviews a valuable role of sigma receptors is as mediators of pain-relieving mechanisms, and therefore they provide pharmacologic targets for the discovery and development of novel analgesic agents [ 2 , 3 ]. Conventional analgesic therapy and medications suffer from well-known challenges, such as insufficient clinical efficacy, worrisome adverse effects, or problems with abuse.…”

Section: Introductionmentioning

confidence: 99%

Bispecific Sigma1R-Antagonist/MOR-Agonist Compounds for Pain

Raffa,

Pergolizzi

2024

Recent research has significantly advanced an understanding of sigma receptors, which consist of two distinct subtypes designated as S1R and S2R (s1R and s2R gene products, respectively). Both subtypes have recently been cloned and their crystal structures have been published. As a result, highly selective S1R and S2R agonist and antagonist ligands are now available. Unlike the confusion generated from prior use of nonselective 'sigma' compounds, these tool compounds have begun to add clarity about the function of sigma receptors in health and disease.The discovery of compounds with high-affinity (nM range) S1R/S2R or S2R/S1R subtype selectivity (>100fold), and selectivity over off-target sites (>1,000-fold) has brought the study of sigma receptor pharmacology into the modern era. Computer modeling has contributed to a better understanding of the binding processes, structural requirements for chemical synthesis, and potential therapeutic uses. Several lines of evidence converge on pain as a therapeutic target for S1R-antagonists (as single mechanism or as part of a multi-mechanistic approach). We highlight here some compounds reported over the past few years that have promise for use as analgesics, specifically some mono-mechanistic S1R-antagonists, and some that are 'bispecific', i.e., have more than one mechanism of action, for example, complementary action of the mu-opioid receptor (MOR). We concentrate on some compounds that are further along in development, in particular, some of the bispecific S1R-antagonist/MOR-agonist compounds.