Pain relievers, including opioids, may alleviate pain for a short time but do not work well for chronic pain, which is one of the most prevalent, disabling and costly health problems in the United States today. The societal costs of pain exceed the annual combined costs of heart disease, diabetes and cancer. Over 40% of Americans suffer from chronic pain, and last year more Americans died of pain-related drug overdoses (more than 70,000) than at the height of the U.S. acquired immunodeficiency syndrome (AIDS) epidemic in 1994-1995. Chronic pain is poorly treated with opioid analgesics, that are effective in only half of these cases, and is accompanied by risks of serious adverse effects including addiction or overdose/death. (Volkow & McLellan, 2017).
Our RAP’s (receptor active peptides) block the inflammation that damages nerves and causes neuropathic, diabetic and other types of pain (ref’s below). Persistent pain is frequently accompanied, indeed caused by chronic inflammation. Activation of the innate immune CCR5 receptor desensitizes the mu opioid receptor (Szabo, 2002, Chen, 2007) to increase pain, while blocking CCR5 potentiates opioid receptor activity to deliver better pain relief at lower opioid doses (Inan, 2018, Eisenstein, 2020). In animal studies our CCR2/5/8 antagonist peptide RAP-103 prevents and reverses neuropathic pain with no need for opioids (Padi, 2012). When opioids are used with RAP-103 opioid efficacy is increased, allowing lower doses to be used to treat acute pain.
Diabetic peripheral neuropathy (DPN) is a frequent complication of diabetes associated with innate immune activation in which individuals experience chronic, debilitating pain that substantially impairs quality of life. In addition, many of the currently available drugs are often not well tolerated by the patients, due to their central nervous system or gastrointestinal side effects and up to 60% of patients stop their medications due to these side effects, or lack of efficacy. The rapidly increasing prevalence of diabetes and DNP, as well as the limitations of the available therapies, makes treatment of DNP a significant unmet medical need.
Recent publications reporting pain benefits for DAPTA & RAP-103
González-Rodríguez, S., M.G. Álvarez, M. García-Domínguez, A. Lastra, R. Cernuda-Cernuda, A.R. Folgueras, M.T. Fernández-García, A. Hidalgo, A. Baamonde, and L. Menéndez. 2017. Hyperalgesic and hypoalgesic mechanisms evoked by the acute administration of CCL5 in mice. Brain Behav Immun.
Hang, L.H., S.N. Li, X. Dan, W.W. Shu, H. Luo, and D.H. Shao. 2016. Involvement of Spinal CCR5/PKCγ Signaling Pathway in the Maintenance of Cancer-Induced Bone Pain. Neurochem Res. 10.1007/s11064-016-2108-5.
Lee, Y.K., D.Y. Choi, Y.Y. Jung, Y.W. Yun, B.J. Lee, S.B. Han, and J.T. Hong. 2013. Decreased pain responses of C-C chemokine receptor 5 knockout mice to chemical or inflammatory stimuli. Neuropharmacology. 67:57-65.
Lu, Y., B.C. Jiang, D.L. Cao, L.X. Zhao, and Y.L. Zhang. 2017. Chemokine CCL8 and its receptor CCR5 in the spinal cord are involved in visceral pain induced by experimental colitis in mice. Brain Res Bull. 135:170-178.
Padi, S.S., X.Q. Shi, Y.Q. Zhao, M.R. Ruff, N. Baichoo, C.B. Pert, and J. Zhang. 2012. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. Pain. 153:95-106. 10.1016/j.pain.2011.09.022.
Pevida, M., A. Lastra, A. Meana, A. Hidalgo, A. Baamonde, and L. Menendez. 2014. The chemokine CCL5 induces CCR1-mediated hyperalgesia in mice inoculated with NCTC 2472 tumoral cells. Neuroscience. 259:113-125.
Saika, F., N. Kiguchi, Y. Kobayashi, Y. Fukazawa, and S. Kishioka. 2012. CC-chemokine ligand 4/macrophage inflammatory protein-1beta participates in the induction of neuropathic pain after peripheral nerve injury. Eur J Pain. 16:1271-1280.