Background & Aims
Most currently available analgesics have either poor therapeutic efficacy or severe adverse effects, including for opioids a high abuse liability (Woolf, 2010; Yekkirala, et al 2017). Efforts to develop new analgesics following standard single target-focused drug discovery have mostly met with little success. We now propose a polypharmacology approach for achieving nociceptor-specific physiological modulation. The aim is to selectively block nociceptors, with little or no effect on other excitable cells, increasing efficacy and preventing adverse effects and addiction risk. To evaluate this we have tested for positive interactions of individual compounds that act on different ion channel targets expressed by nociceptors.
Methods
Male C57BL6/J mice were treated with intraperitoneal injection of a single, double, or triple combination of individual compounds that each act only on a single ion channel expressed by nociceptors. Hot plate withdrawal latency at 52oC was measured 45 minutes after the drug treatment and the time the mice spent licking and biting the hindpaw in response to an intraplantar injection of capsaicin (TRPV1 activator) measured for 3 minutes. Quantification was done using a novel data acquisition and analysis platform that provides automated, quantitative, and objective measures of rodent behavior in an observer-independent and unbiased fashion in freely moving animals (Zhang et al, Pain, 2022). Side effects such as distance traveled, locomoting time and not moving time were also quantified.
Results
Single intraperitoneal administration of single nociceptor ion channel compounds at increasing doses did not produce analgesia on either the hot plate or capsaicin tests except at very high doses with side effects. A double or triple combination of these compounds was able, however, to increase the withdrawal latency on the hot plate test and decrease the nocifensive behavior in the capsaicin test at doses that were not effective when administered alone. Side effects were prevented when using both the double and triple polypharmacological approach.
Conclusions
A polypharmacology treatment with compounds that act on different nociceptor ion channels have synergic analgesic effects by more effectively selectively silencing nociceptors. Adverse effects that manifest when high doses of single drugs are administered were prevented due to the requirement of low individual doses in the combinations.
References
Woolf CJ. Overcoming obstacles to developing new analgesics. Nat Med. 2010 Nov;16(11):1241–1247.
Yekkirala AS, Roberson DP, Bean BP, Woolf CJ. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov. 2017 Nov;16(11):810.
Zhang, Zihea,b; Roberson, David P.a,b; Kotoda, Masakazua,b; Boivin, Brunoa,b; Bohnslav, James P.b; González-Cano, Rafaela,b; Yarmolinsky, David A.a,b; Turnes, Bruna Lenfersa,b; Wimalasena, Nivanthika K.a,b; Neufeld, Shay Q.b; Barrett, Lee B.a,b; Quintão, Nara L. M.a,b; Fattori, Victora,b; Taub, Daniel G.a,b; Wiltschko, Alexander B.b; Andrews, Nick A.a,b; Harvey, Christopher D.b; Datta, Sandeep Robertb; Woolf, Clifford J.a,b,*. Automated preclinical detection of mechanical pain hypersensitivity and analgesia. PAIN 163(12):p 2326-2336, December 2022.
Presenting Author
Bruna Turnes
Poster Authors
Bruna Turnes
PT, MSc, PhD
Boston Children's Hospital
Lead Author
Maryam Arab
MD
Lead Author
Selwyn Jayakar
Boston Children's Hospital
Lead Author
Rasheen Powell
Ph.D.
Boston Childrens Hospital
Lead Author
Jaehoon Shim
Lead Author
Xiao Ma
PhD
Lead Author
Biyao Zhang
BS
Lead Author
Zihe Zhang
PhD
Lead Author
Omer Barkai
PhD
Lead Author
Lee Barret
PhD
Lead Author
Bruce Bean
PhD
Lead Author
Peter Sorger
Ph.D.
Harvard Medical School
Lead Author
Clifford Woolf
MB
Boston Childrens Hospital
Lead Author
Topics
- Treatment/Management: Pharmacology: Non-opioid