Abstract
Neuropathic pain can develop after nerve injury, leading to a chronic condition with spontaneous pain and hyperalgesia. Pain is typically restricted to the side of the injured nerve, but may occasionally spread to the contralateral side, a condition that is often referred to as mirror-image pain. Mechanisms leading to mirror-image pain are not completely understood, but cannabinoid CB2 receptors have been implicated. In this study, we use genetic mouse models to address the question if CB2 receptors on neurons or on microglia/macrophages are involved. First, we show that a GFP reporter protein under control of the CB2 promoter is induced upon partial sciatic nerve ligation in spinal cord, dorsal root ganglia, and highest in sciatic nerve macrophages, but not in neurons. Mice which lack CB2 receptors specifically on myeloid cells (microglia, macrophages) developed a mirror-image allodynia [treatment F1,48 = 45.69, p < 0.0001] similar to constitutive CB2 receptor knockout mice [treatment F1,70 = 92.41, p < 0.0001]. Such a phenotype was not observed after the deletion of CB2 from neurons [treatment F1,70 = 0.1315, p = 0.7180]. This behavioral pain phenotype was accompanied by an increased staining of microglia in the dorsal horn of the spinal cord, as evidenced by an enhanced Iba 1 expression [CB2KO, p = 0.0175; CB2-LysM, p = 0.0425]. Similarly, myeloid-selective knockouts showed an increased expression of the leptin receptor in the injured ipsilateral sciatic nerve, thus further supporting the notion that leptin signaling contributes to the increased neuropathic pain responses of CB2 receptor knockout mice. We conclude that CB2 receptors on microglia and macrophages, but not on neurons, modulate neuropathic pain responses.
Highlights
Preparations of Cannabis sativa have been used for millennia to treat various pain conditions
We used cell-selective cannabinoid receptor 2 (CB2) knockout mouse lines in order to assess if CB2 receptor expression on neurons or myeloid cells, or both, is relevant for neuropathic pain development
We used different genetic mouse models to demonstrate that CB2 receptors on myeloid cells modulate neuroinflammatory responses after partial sciatic nerve ligation
Summary
Preparations of Cannabis sativa have been used for millennia to treat various pain conditions. Enhanced CB2 signaling in mice overexpressing CB2 receptors in microglia and neurons reduced the manifestation of neuropathic pain symptoms[26]. The deletion of CB2 resulted in an enhanced neuroinflammatory response after sciatic nerve injury and in mirror-image pain, as evidenced by the development of tactile allodynia on the contralateral side of the injured nerve[26]. Www.nature.com/scientificreports promotes neuropathic pain via modulating CB2 signaling. Mice with a deletion of the CB2 receptor showed an increase in leptin receptor expression on the ipsi- and contralateral sciatic nerve. Because CB2 receptors are expressed on neurons, as well as macrophages and microglia after sciatic nerve injury, it is not clear on which cells CB2 is acting during neuropathic pain.
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