The compound URB937, which we disclose in the present study, is a potent FAAH inhibitor that does not readily enter the CNS and thus interrupts anandamide deactivation only in peripheral tissues. Despite this restricted range of action, URB937 causes marked antinociceptive effects in rodent models of acute and persistent pain, which are prevented by cannabinoid CB1 receptor blockade. These findings suggest that inhibition of peripheral FAAH activity magnifies an endogenous analgesic mechanism, mediated by anandamide, which regulates the transmission of emerging pain signals to the spinal cord and the brain.
We hypothesize that peripheral anandamide acts as a diffuse paracrine signal to modulate the intensity of pain stimuli as they arise in damaged tissues. Two lines of evidence support this idea. Firstly, signals generated by inflammation and neural injury can trigger the local production and release of anandamide. For example, membrane depolarization and activation of TRPV-1 channels each stimulates anandamide formation in cultures of sensory neurons30
, while activation of Toll-like receptor 4 causes a similar effect in macrophages31
. These signals, and likely others that remain to be identified, may contribute to the elevations in peripheral anandamide documented in animal models of spinal nerve injury and inflammation8,11
as well as in painful human conditions such as complex regional pain syndrome9
. Secondly, CB1
receptors are broadly distributed throughout mammalian tissues and organs. In particular, they are expressed in primary sensory neurons of heterogeneous sizes and are transported to peripheral nerve endings32,33
. There, CB1
receptor activation may be both necessary to maintain normal pain thresholds8
and sufficient to exert marked antinociceptive effects3,6
receptors present on pain-sensing terminals may mediate the analgesic and anti-inflammatory actions of locally produced anandamide through their inhibitory influence on the release of excitatory neuropeptides34
. Other receptors are likely to contribute, along with CB1
, to anandamide signaling in response to injury. Two candidates are CB2
and PPAR-α, which are present in immune cells and peripheral sensory neurons, and act synergistically with CB1
to reduce pain3,23,24,35,36
. Our results suggest, indeed, that CB1
receptors cooperate both with PPAR-α, to modulate visceral pain in the acetic acid model, and with CB2
, to reduce edema in the carrageenan model. Importantly, however, CB1
receptors appear to play an exclusive role in mediating the analgesic effects of URB937 in models of neuropathic and inflammatory pain.
Mutant mice in which FAAH expression is selectively disrupted in non-neuronal cells, but is preserved in peripheral and central neurons, display a striking phenotype in which normal nociceptive transmission is accompanied by reduced responsiveness to pro-inflammatory triggers37
. A plausible explanation for this finding is that the signaling activity of anandamide at peripheral nociceptive neurons is influenced by FAAH localized to the nociceptors themselves, rather than to neighboring non-neural cells. This view is consistent with the observation that peripheral axotomy induces FAAH expression in large-sized sensory neurons of the dorsal root ganglia, a response that is expected to extend the co-localization of FAAH with CB1
receptors and thus enhance the ability of this enzyme to terminate anandamide signaling38
Direct activation of peripheral cannabinoid receptors causes profound analgesic effects in experimental models of pain2,39
. Our findings indicate that significant analgesia can also be obtained by magnifying the intrinsic activity of an anandamide-based signaling system involved in the dynamic regulation of nociceptive homeostasis outside the CNS. These findings offer new insights into the intrinsic control of pain and might be exploited therapeutically to develop analgesic agents devoid of central side effects.