Role of the cannabinoid receptor 2 in the development of surgical neuropathic pain

Abstract

When normal nociceptive pain becomes chronic, it loses its protective function and causes a general pain hypersensitivity. Neuropathic pain is one type of chronic pain, which is caused by various diseases or physical injury of the somatosensory nervous system. The two main symptoms include hyperalgesia, describing increased sensitivity to pain, or allodynia, the sensation of pain after an innocuous stimulation. These symptoms result from a maladaptive plasticity of the nociceptive system. In recent years, many studies could confirm a contribution of the endocannabinoid system in nociception. In particular, the CB2 receptor is known be located on immune cells and to regulate inflammation. Since inflammation of the somatosensory nervous system is a key component of neuropathic pain, I was interested in the pain phenotype of mice with a constitutive or conditional CB2 deletion. Previous studies demonstrated that mice with a constitutive CB2 deletion (CB2KO) develop increased mechanical allodynia on the non-injured side after induction of neuropathic pain through partial sciatic nerve ligation.<br /> I analyzed neuropathic pain development in conditional CB2 knockout mice, lacking the CB2 receptor in myeloid cells (e.g. microglia and macrophages, CB2-LysM) or in neurons (CB2-Syn) only. CB2-LysM mice showed the same enhanced allodynia on the non-injured side as observed in CB2KO animals. This effect was not measured in CB2-Syn mice. I could confirm this finding through histological studies measuring microgliosis in the dorsal horn of the lumbar spinal cord. Microgliosis was increased on both sides of the spinal cord in CB2KO and CB2-LysM mice. To confirm the cellular distribution of CB2, I used CB2-GFP mice, which reveal a GFP signal in all CB2-expressing cells. A strong expression was found in the sciatic nerve, dorsal root ganglion and lumbar spinal cord that colocalized with microglial marker Iba1 but not with neuronal marker synapsin. These results indicate the expression of the CB2 receptor on microglia cells.<br /> The CB2 receptor can be activated through the two main endocannabinoids 2-AG and anandamide. I investigated the contribution of Daglα the main synthesizing enzyme for 2-AG, in thermal, mechanical and neuropathic pain behavior. Contrary to our expectations, mice lacking Daglα showed the same pain phenotype as normal WT animals. I suspect an 2-AG independent activation of CB2 during neuropathic pain, which would serve to counteract the inflammation.