Distinct from data in the current report, increased FAAH IR was observed in large diameter DRG neurons following sciatic nerve axotomy or L5 spinal nerve transection (Lever et al. 2009). However, animal models of peripheral axotomy can result in different protein expression profiles in spinal cord and DRG compared

to intact damaged axons, as is the case with CCI. These observed differences are frequently reported in different animal models of pathological pain (DeLeo et al. 2007). DRG satellite cells form a distinct sheath that completely surround sensory neurons, and together Inhibitors,research,lifescience,medical with the neuron, create a discrete morphological (Hanani 2005) and a functional unit (Takeda et al. 2009). Satellite DRG glia have gained increasing recognition for altering nociceptive transmission by expressing

and responding to several proinflammatory cytokines including IL-1β (Takeda et al. 2008, 2009). Indeed, IL-1β rapidly Inhibitors,research,lifescience,medical activates nociceptive cells in a p38MAPK-dependent manner Inhibitors,research,lifescience,medical (Cisplatin concentration Binshtok et al. 2008). The current report supports these reports, as increased expression of p-p38MAPK and IL-1β, in addition to GFAP, were present in the DRG of neuropathic animals. We demonstrate that ipsilateral DRG IL-10 expression is significantly decreased during CCI-induced chronic neuropathy. Conversely, i.t. treatment with AM1241 resulted in greater Inhibitors,research,lifescience,medical p-p38MAPK, IL-1β, and IL-10 IR levels that are similar to non-neuropathic control basal values. No IL-10, IL-1β, and p-p38MAPK IR

changes in contralateral DRG were observed during CCI-induced chronic allodynia, suggesting these immune signals in contralateral DRG do not play a significant role in CCI-induced contralateral allodynia. Although AM1241s behavioral effects occur within a relatively short therapeutic half-life (~1.5 h), these data reveal crucial findings that may support the development Inhibitors,research,lifescience,medical of longer lasting, “next generation” CB2R agonists to produce therapeutic ADAMTS5 pain control. An advantage of a short therapeutic half-life is the capability to tightly regulate drug loading doses and potential unwanted side effects. Oral formulations easily allow for repeated dosing at discrete intervals. Additionally, a short half-life for i.t. efficacy localized to the spinal cord may be advantageous as it may remain localized to spinal canal, avoiding potential global inhibition of important immune function. Prior reports together with the data presented here support that the actions of AM1241 are highly effective to control pathological pain when delivered either peripherally or by i.t. administration.