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