Monoacylglycerol lipase (MGL) is a multifunctional serine hydrolase, which terminates
anti-nociceptive endocannabinoid signaling and promotes pro-nociceptive prostaglandin
signaling. Accordingly, both acute nociception and its sensitization in chronic pain
models are prevented by systemic or focal spinal inhibition of MGL activity. Despite
its analgesic potential, the neurobiological substrates of beneficial MGL blockade
have remained unexplored. Therefore, we examined the regional, cellular and subcellular
distribution of MGL in spinal circuits involved in nociceptive processing. All immunohistochemical
findings obtained with light, confocal or electron microscopy were validated in MGL-knockout
mice. Immunoperoxidase staining revealed a highly concentrated accumulation of MGL
in the dorsal horn, especially in superficial layers. Further electron microscopic
analysis uncovered that the majority of MGL-immunolabeling is found in axon terminals
forming either asymmetric glutamatergic or symmetric gamma-aminobutyric acid/glycinergic
synapses in laminae I/IIo. In line with this presynaptic localization, analysis of
double-immunofluorescence staining by confocal microscopy showed that MGL colocalizes
with neurochemical markers of peptidergic and non-peptidergic nociceptive terminals,
and also with markers of local excitatory or inhibitory interneurons. Interestingly,
the ratio of MGL-immunolabeling was highest in calcitonin gene-related peptide-positive
peptidergic primary afferents, and the staining intensity of nociceptive terminals
was significantly reduced in MGL-knockout mice. These observations highlight the spinal
nociceptor synapse as a potential anatomical site for the analgesic effects of MGL
blockade. Moreover, the presence of MGL in additional terminal types raises the possibility
that MGL may play distinct regulatory roles in synaptic endocannabinoid or prostaglandin
signaling according to its different cellular locations in the dorsal horn pain circuitry.
