The study investigates the role of endogenous cannabinoids in controlling pain initiation. Researchers found that anandamide and palmitoylethanolamide (PEA) interact with cannabinoid receptors outside the central nervous system to reduce pain responses. Anandamide, an endogenous cannabinoid, and PEA, a related compound, both activate peripheral cannabinoid receptors, with anandamide targeting CB1-like receptors and PEA targeting CB2-like receptors. When administered together, these compounds synergistically reduce pain responses more potently than either alone. The study used the formalin test, a behavioral model of injury-induced pain, to demonstrate that anandamide and PEA inhibit pain behavior by activating peripheral cannabinoid receptors. The results suggest that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation, and that locally generated anandamide and PEA may mediate this effect. The findings indicate that endogenous cannabinoids may contribute to the control of pain transmission within the central nervous system. The study also highlights the potential of peripheral cannabinoid agonists for pain management without the side effects associated with centrally acting cannabinoids or opioids.The study investigates the role of endogenous cannabinoids in controlling pain initiation. Researchers found that anandamide and palmitoylethanolamide (PEA) interact with cannabinoid receptors outside the central nervous system to reduce pain responses. Anandamide, an endogenous cannabinoid, and PEA, a related compound, both activate peripheral cannabinoid receptors, with anandamide targeting CB1-like receptors and PEA targeting CB2-like receptors. When administered together, these compounds synergistically reduce pain responses more potently than either alone. The study used the formalin test, a behavioral model of injury-induced pain, to demonstrate that anandamide and PEA inhibit pain behavior by activating peripheral cannabinoid receptors. The results suggest that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation, and that locally generated anandamide and PEA may mediate this effect. The findings indicate that endogenous cannabinoids may contribute to the control of pain transmission within the central nervous system. The study also highlights the potential of peripheral cannabinoid agonists for pain management without the side effects associated with centrally acting cannabinoids or opioids.