Pain is one of the most fundamental mechanisms of self-preservation. Acute pain, unpleasant as it may be, is a highly effective way for our body to indicate that something is wrong. Chronic pain, however, is a much more complicated condition that provides an excellent challenge for a wide variety of health care professionals, such as neurologists, orthopedics, rheumatologists, oncologists, psychologists, and physiotherapists. It may be the result of different pathological causes, including injury, spinal cord deformations, peripheral neuropathy, cancer, and many others. 

Depending on the etiology of chronic pain, different medical disciplines are involved in its management. For example, osteoarthritic pain is usually managed effectively by orthopedic surgery. Similarly, spinal cord injuries or deformities can be resolved by neuro-surgical procedures in certain instances. Beyond surgery, there are those patients for whom a surgical procedure is either not useful, not available, or not indicated. These patients are managed by chronic pain specialists with the use of pain-relieving medications, as well as physiotherapy and psychological support. 

Since the discovery of aspirin and morphine in the late 19th century, and that of acetaminophen (aka paracetamol) a few years later, the pharmaceutical management of pain has lead to the development of NSAIDs, opioids, and corticosteroids. Additionally, several different classes of medications with nerve stabilizing properties, such as carbamazepine, pregabalin and duloxetine, have been used in the treatment of neuropathic pain. 

However, available medications are not devoid of adverse drug reactions. Acetaminophen is known for its hepatotoxic effects with long term use. Similarly, NSAIDs are known to adversely affect the gastro-intestinal (COX-1) and cardio-vascular(COX-2) systems. These adverse effects restrict the use of acetaminophen and NSAIDs in the management of acute pain, since chronic consumption of these medications may lead to severe complications and even death. Furthermore, the use of opioids is related to the development of addiction and tolerance. Finally, there are several instances when the desired therapeutic outcome is not achieved due to pain being resistant to available medication treatments.     

Anyone who has ever had to deal with the clinical management of chronic pain will admit that it is a very challenging field. Something as benign as trigeminal neuralgia, in a sense that it does not present a threat to the patient’s life, can be unresponsive to every available treatment. This can result in a significant deterioration in terms of quality of life. It should, therefore, come across that any new developments in the field of pain management would be of great value to clinicians around the world. 

Study on chronic pain management

In a recent article published by the Journal of Neuroscience, investigators used several different rodent models to identify a new potential target for novel chronic pain management treatments 1. Regulator of G protein Signaling 4 (RGS4) is a protein that regulates G protein signalling. In humans, it is encoded by the RGS 4 gene. RGS 4 has been implicated to play a role in the development of schizophrenia as well as the development of mu-opioid receptor tolerance. 2,3

In this report, the authors were able to demonstrate that RGS 4 plays a crucial role in the creation, intensity and maintenance of pain, regardless of whether it was induced by inflammation or injury. The investigators utilized a rodent model that was genetically engineered to inhibit the RSG 4 gene and were able to demonstrate that preventing the actions of RSG 4 led to faster recovery times following both mechanical as well as cold stimuli. Furthermore, this protein seemed to play an essential role in the progression of acute to sub-acute pain, since it was demonstrated the expression of RSG 4 is up-regulated in chronic pain syndromes. Interestingly, previous reports had indicated that RSG 4 interferes with the effectiveness of several different medications, such as fentanyl, methadone, and desipramine. 4,5


The investigators concluded that RSG4 plays a pivotal role in the creation and maintenance of chronic pain. This action seems to be involved in several different biochemical processes throughout the body, rendering its inhibition a potentially attractive target for pharmaceutical interventions. Naturally, we are still a long way from utilizing the valuable insights of this trial in clinical practice. However, RSG 4 seems to pose an attractive target for further experimental as well as clinical trials. 

Several studies have evaluated the epidemiology six as well as the impact of chronic pain on quality of life 7,8. Without a doubt, chronic pain is a significant public health issue with a substantial negative impact. There is a clear need for the development of novel treatments aimed at potentially new molecular targets. Adding such new agents to our arsenal could provide a valuable tool in our efforts to improve the lives of those who suffer.


  1. Avrampou K, Pryce KD, Ramakrishnan A, Sakloth F, Gaspari S, Serafini RA, Mitsi V, Polizu C, Swartz C, Ligas B, Richards A, Shen L, Carr FB, Zachariou V. RGS4 Maintains Chronic Pain Symptoms in Rodent Models. J Neurosci. 2019 Oct 16;39(42):8291-8304. DOI: 10.1523/JNEUROSCI.3154-18.2019. Epub 2019 Jul 15. PubMed PMID: 31308097; PubMed Central PMCID: PMC6794935.
  2. Stefanis NC, Trikalinos TA, Avramopoulos D, Smyrnis N, Evdokimidis I, Ntzani EE, Hatzimanolis A, Ioannidis JP, Stefanis CN. Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level. Behav Brain Funct. 2008 Oct 3;4:46. DOI: 10.1186/1744-9081-4-46. PubMed PMID: 18834502; PubMed Central PMCID: PMC2572614.
  3. Hooks SB, Martemyanov K, Zachariou V. A role of RGS proteins in drug addiction. Biochem Pharmacol. 2008 Jan 1;75(1):76-84. Epub 2007 Aug 11. Review. PubMed PMID: 17880927.
  4. Han MH, Renthal W, Ring RH, Rahman Z, Psifogeorgou K, Howland D, Birnbaum S, Young K, Neve R, Nestler EJ, Zachariou V. Brain regions specific actions of a regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia. Biol Psychiatry. 2010 Apr 15;67(8):761-9. DOI: 10.1016/j.biopsych.2009.08.041. Epub 2009 Nov 14. PubMed PMID: 19914603; PubMed Central PMCID: PMC3077672.
  5. Stratinaki M, Varidaki A, Mitsi V, Ghose S, Magida J, Dias C, Russo SJ, Vialou V, Caldarone BJ, Tamminga CA, Nestler EJ, Zachariou V. Regulator of G protein signaling 4 [corrected] is a crucial modulator of antidepressant drug action in depression and neuropathic pain models. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8254-9. DOI: 10.1073/pnas.1214696110. Epub 2013 Apr 29. Erratum in: Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11660. PubMed PMID: 23630294; PubMed Central PMCID: PMC3657820.
  6. Johannes CB, Le TK, Zhou X, Johnston JA, Dworkin RH. The prevalence of chronic pain in United States adults: results of an Internet-based survey. J Pain. 2010 Nov;11(11):1230-9. DOI: 10.1016/j.jpain.2010.07.002. Epub 2010 Aug 25. PubMed PMID: 20797916. 
  7. Ferini-Strambi L. Sleep disorders in multiple sclerosis. Handb Clin Neurol. 2011;99:1139-46. doi: 10.1016/B978-0-444-52007-4.00025-4. PubMed PMID: 21056246.
  8. McBeth J, Chiu YH, Silman AJ, Ray D, Morriss R, Dickens C, Gupta A, Macfarlane GJ. Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents. Arthritis Res Ther. 2005;7(5): R992-R1000. Epub 2005 Jun 17. PubMed PMID: 16207340; PubMed Central PMCID: PMC1257426.