The ECS is expressed extensively throughout the PNS, with CB1, CB2, and TRPV1 all playing a role in nociception. AEA on peripheral nerves reduced pain in animal models via CB1. 2-AG and PEA have also been shown to be capable of reducing peripheral pain via CB2 receptor across a variety of pain modalities. In some circumstances, this action is mediated peripherally by CB1 and CB2 receptor’s activated release of norepinephrine (NE). CB2 receptor expression upregulation is triggered in sciatic nerve ligation studies, potentially as a mechanism to prevent sensitization and chronic pain development. CB1 upregulation in the DRG has been shown in response to oxaliplatin exposure and prevented neuropathy development. Endocannabinoid concentrations in the spinal cord are increased by the animal models of neuropathy, and boosting levels further by blocking degradation enzymes was as effective as opiates in decreasing pain and superior to gabapentin. SNPs in FAAH gene have been shown to causes changes in pain and cold sensitivities. Interactions with TRPV1 receptor also appear to be important in the prevention/development of chronic pain. Hemopressin, the pepcan, prevents neuropathy in rats when given orally. CB2 knockout mice have higher amounts of activated immune cells in the spinal cord and are more susceptible to neuropathy, indicating a role of inflammation. Intrathecal administration of CB1 receptor blockers results in the development of hyperalgesia in the absence of injury, indicating a tonic role of the ECS in prevention of pain sensitization. Part of the antinociceptive effective in the spinal cords is also mediated via activation of descending neurons from the CNS as evidenced by pain relief with injection of CB1 agonist in the ventricle and partial blockage of effect in rats with their spinal cords severed above the area of study. The ECS was capable of both boosting release of endogenous opiates and preventing hyper-analgesia caused by chronic exogenous opiate administration.