Microglia-independent peripheral neuropathic pain in male and female mice

ABSTRACT: The dominant view in the field of pain is that peripheral neuropathic pain is driven by microglia in the somatosensory processing region of the spinal dorsal horn. Here, to the contrary, we discovered a form of neuropathic pain that is independent of microglia. Mice in which the nucleus pulposus (NP) of the intervertebral disc was apposed to the sciatic nerve developed a constellation of neuropathic pain behaviours: hypersensitivity to mechanical, cold, and heat stimuli. However, NP application caused no activation of spinal microglia nor was pain hypersensitivity reversed by microglial inhibition. Rather, NP-induced pain hypersensitivity was dependent on cells within the NP which recruited macrophages to the adjacent nerve. Eliminating macrophages systemically or locally prevented NP-induced pain hypersensitivity. Pain hypersensitivity was also prevented by genetically disrupting the neurotrophin brain-derived neurotrophic factor selectively in macrophages. Moreover, the behavioural phenotypes as well as the molecular mechanisms of NP-induced pain hypersensitivity were not different between males and females. Our findings reveal a previously unappreciated mechanism for by which a discrete peripheral nerve lesion may produce pain hypersensitivity, which may help to explain the limited success of microglial inhibitors on neuropathic pain in human clinical trials

Early blockade of joint inflammation with a fatty acid amide hydrolase inhibitor decreases end-stage osteoarthritis pain and peripheral neuropathy in mice

Abstract Background The endocannabinoid system has been shown to reduce inflammatory flares and pain in rodent models of arthritis. A limitation of endocannabinoids is that they are rapidly denatured by hydrolysing enzymes such as fatty acid amide hydrolase (FAAH) which renders them physiologically inert. Osteoarthritis (OA) is primarily a degenerative joint disease; however, it can incorporate mild inflammation and peripheral neuropathy. The aim of this study was to determine whether early blockade of FAAH bioactivity could reduce OA-associated inflammation and joint neuropathy. The ability of this treatment to prevent end-stage OA pain development was also tested. Methods Physiological saline or sodium monoiodoacetate (MIA; 0.3 mg) was injected into the right knee of male C57Bl/6 mice (20–42 g) and joint inflammation (oedema, blood flow and leukocyte trafficking) was measured over 14 days. Joint inflammation was also measured in a separate cohort of animals treated on day 1 with either saline or the FAAH inhibitor URB597 (0.03–0.3 mg/kg topical onto the knee joint). In other experiments, von Frey hair tactile sensitivity was determined on days 1 and 14 in MIA-injected mice treated prophylactically with URB597 (0.3 mg/kg s.c. over the knee joint on days 0–3). Saphenous nerve myelination was also assessed in these animals on day 14 by G-ratio analysis. Results Intra-articular injection of MIA caused an increase in joint oedema (P < 0.0001), blood flow (P < 0.05), leukocyte rolling (P < 0.05) and adherence (P < 0.001) on day 1 after treatment which subsequently resolved over later time points. This acute inflammatory response was ameliorated by local URB597 treatment. Prophylactic local administration of URB597 prevented MIA-induced saphenous nerve demyelination, and chronic joint pain was also attenuated. Conclusions These data indicate that local inhibition of FAAH in MIA-injected knees can reduce acute inflammatory changes associated with the model. Prophylactic treatment of OA mice with the endocannabinoid hydrolysis inhibitor URB597 was also shown to be neuroprotective and prevented the development of joint pain at later time points