Joint Mobilization Relieved Post-Surgical Pain Through Cannabinoid Receptors, Enhanced by FAAH and MAGL Inhibitors | Research

The takeaway

Ankle joint mobilization reduced post-surgical pain in mice through both CB1 and CB2 cannabinoid receptors at different anatomical levels, and the pain-relieving effect lasted significantly longer when endocannabinoid-degrading enzymes were blocked.

Read this if you are interested in why physical therapy helps with pain and how the endocannabinoid system is involved.

Endocannabinoid enzyme inhibitors significantly extended the pain relief from joint mobilization

What the researchers found

Mice underwent plantar incision surgery and received ankle joint mobilization 24 hours later. The mobilization reduced mechanical hypersensitivity, and this effect was mediated by cannabinoid receptors. CB1 receptor involvement was confirmed at the spinal (intrathecal) and systemic (intraperitoneal) levels but not at the peripheral (intraplantar) level. CB2 receptors operated peripherally and systemically but not spinally.

When mice were pretreated with either URB937 (FAAH inhibitor) or JZL184 (MAGL inhibitor), the pain-relieving effect of joint mobilization lasted significantly longer. This demonstrated that physical therapy activates the endocannabinoid system, and boosting endocannabinoid levels pharmacologically extends the therapeutic benefit.

Why it matters

This study provides a mechanistic explanation for why physical therapy reduces pain: it activates the endocannabinoid system. The finding that endocannabinoid-boosting drugs extend this effect opens the door to combining physical therapy with pharmacological endocannabinoid enhancement for better post-surgical pain management.

The numbers in context

Joint mobilization: 9 minutes. CB1 involvement: spinal and systemic. CB2 involvement: peripheral and systemic. FAAH inhibitor URB937: 0.01-1 mg/kg extended mobilization effect. MAGL inhibitor JZL184: 0.016-16 mg/kg extended mobilization effect.

How the study worked

Mouse plantar incision model. Ankle joint mobilization (9 minutes) 24 hours post-surgery. CB1 antagonist AM281 and CB2 antagonist AM630 administered by three routes (systemic, spinal, peripheral). FAAH inhibitor URB937 and MAGL inhibitor JZL184 tested as adjuncts to mobilization.

What this study cannot tell us

Mouse model of surgical pain may not translate directly to human physical therapy. The ankle mobilization protocol is simplified compared to clinical physical therapy. Acute post-surgical pain is one specific pain type. The drug doses used may not be clinically feasible in humans.

How to read the evidence

Comprehensive animal study with multiple receptor and route assessments; moderate preclinical evidence.

When this study was published

Published in 2013. The role of endocannabinoids in exercise and physical therapy continues to be explored.

The bigger picture

This study bridges physical therapy and pharmacology by showing they can work synergistically through the endocannabinoid system. It validates what many pain patients experience: movement helps pain, and the mechanism involves the body's own cannabinoid system.

Questions still open

Could combining physical therapy with low-dose endocannabinoid-boosting drugs improve human post-surgical outcomes? Does exercise activate the same cannabinoid pathways? Would cannabis use before physical therapy enhance or diminish the endocannabinoid response?

Common questions

Does physical therapy activate the endocannabinoid system?

Yes, according to this mouse study. Joint mobilization reduced pain through cannabinoid receptors, meaning the physical manipulation itself triggered endocannabinoid release. This is consistent with research showing exercise produces endocannabinoids, contributing to "runner's high." The study suggests physical therapy works partly by harnessing the body's own cannabis-like molecules.

Could drugs make physical therapy work better?

This study found that drugs that slow the breakdown of endocannabinoids (FAAH and MAGL inhibitors) significantly extended the pain relief produced by joint mobilization. In principle, taking a medication that boosts endocannabinoid levels before physical therapy could amplify and prolong its pain-relieving effects. This has not been tested in humans yet.

Read the original research

Peripheral and spinal activation of cannabinoid receptors by joint mobilization alleviates postoperative pain in mice.

Neuroscience, 255, 110-21

View on PubMed ↗Publisher’s paper ↗

Citation

Martins, D F; Mazzardo-Martins, L; Cidral-Filho, F J; Gadotti, V M; Santos, A R S. (2013). Peripheral and spinal activation of cannabinoid receptors by joint mobilization alleviates postoperative pain in mice.. Neuroscience, 255, 110-21. https://doi.org/10.1016/j.neuroscience.2013.09.055