Palmitoylethanolamide Attenuates Pain-like Behavior in Factor VIII Deficient Mice

Coagulation factor VIII (FVIII) deficiency gives rise to hemophilia A, which is characterized by spontaneous joint bleeding. Uncontrolled bleeding drives inflammation and release of noxious and neuropathic factors, accompanied by joint degeneration, arthropathy, joint/chronic pain and impairment in physical activity. Thus, an unmet need is to develop strategies to target pain and improve physical activity in hemophilia. Chronic joint pain observed in osteoarthritis (OA) shares features of inflammation and hemarthropathy with hemophilia joint pain. Palmitoylethanolamide (PEA) is being evaluated for joint pain in OA in an interventional clinical trial (NCT05406726), which builds upon a previous double-blind, placebo-controlled evaluation suggesting its safety, tolerability, and efficacy in alleviating OA joint pain. PEA is an endogenous lipid mediator that interacts with the endogenous cannabinoid system to alleviate chronic pain, inflammation and signs of neuropathy without the intoxicating effects of cannabinoids. We reported that PEA reduced chronic pain in a mouse model of sickle cell disease (Argueta et al., Blood 2021), which presents with release of cell free heme, consequent inflammation and tissue damage similar to hemophilia. Due to its ability to reduce clinical pain outcomes and its beneficial effects on inflammation, osteoclastogenesis, and neuropathy, PEA may provide substantial benefits as a novel treatment for pain in hemophilia. To test this hypothesis, we utilized FVIII-knockout (KO) mice, which recapitulate features of human hemophilia A including spontaneous bleeding and pain (Cooke et al., J Thromb Haemost 2019), to evaluate the impact of daily PEA treatment on nociceptive and nocifensive behaviors. We treated 12 wks old male control (B6129SF2/J) and FVIII-KO (B6;129S-F8tm1Kaz/J) mice (Jackson Laboratory, Bar Harbor, ME) intraperitoneally with 20 mg/kg/d PEA (Cayman Chemical, Ann Arbor, MI) for 7 days followed by 7 day withdrawal. Mice were weighed and examined for mechanical hyperalgesia by application of Von Frey monofilaments to the plantar surface of the hindpaws (10 repetitions per paw) and weight bearing on pressure-sensitive plates (Incapacitance Tester, Ugo Basile, Gemonio, Italy) at baseline (BL), then after PEA treatment at 1, 4, and 24 hours, days 3 and 7; and after discontinuation of treatment on days 10 and 14. We also measured spontaneous nocifensive behaviors (locomotion, rearing, and grooming) over a 2-minute period in homecage (Generic USB webcam; Streampix 7, Norpix, Montreal, Canada) at BL, days 7 and 14. PEA treatment reduced mechanical hyperalgesia (~60%, P<0.001) in FVIII-KO mice after 1 hour, which continued to improve over 24 hours and was maintained for 7 days of treatment. Following withdrawal, mechanical hyperalgesia was no longer alleviated. These data suggest increased sensory pain in FVIII-KO mice, and that PEA has an analgesic effect. PEA treatment improved stance instability in weight bearing test of FVIII-KO mice (~66%, P<0.05) after 4 hours, which continued to improve over treatment period and persisted after withdrawal, up to day 10. However, improved weight bearing regressed by day 14. Improved weight bearing even after withdrawal of the PEA for 3 days suggests a disease modifying effect perhaps via reduction in joint inflammation, modulation of arthropathy and/other mechanisms. Non-evoked, spontaneous nocifensive behaviors show associations (Pearson correlation, P<0.05) with weight bearing at BL, days 7 and 14 in FVIII-KO mice. Thus, nocifensive behaviors may be a less invasive, indirect measure of weight bearing and joint pain. Body mass was not significantly affected by treatment and subsequent withdrawal. We provide the first evidence that PEA may reduce mechanical hyperalgesia and improve weight bearing in a translational model of hemophilia A. Several clinical evaluations of PEA indicate its safety, even at relatively large doses, and its efficacy in reducing inflammation and pain, which include joint pain and damage observed in OA. Our observations and the availability of PEA as a dietary supplement underscore the need for clinical and preclinical evaluation of PEA for hemophilia pain.

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