Abstract
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 γ-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.
Highlights
To detect and minimize tissue damage, numerous signaling mechanisms operate together in the peripheral, spinal and supraspinal pain circuits (Basbaum et al, 2009)
To determine the spinal circuits in which Monoacylglycerol lipase (MGL) may play a regulatory role in 2-AG and/or prostaglandin signaling, the regional distribution pattern of MGL was first investigated by immunoperoxidase immunohistochemistry
At the light microscopic level, a striking accumulation of dense MGL-positive immunostaining was detected in the dorsal horn of spinal cord sections derived from MGL+/+ mice (Fig. 1A)
Summary
To detect and minimize tissue damage, numerous signaling mechanisms operate together in the peripheral, spinal and supraspinal pain circuits (Basbaum et al, 2009). Persistent noxious stimuli evoke various forms of molecular and cellular adaptations in these signaling processes (Sandk€uhler, 2009). Some may last beyond the resolution of tissue injury leading to chronic pain syndromes; a major conceptual and practical challenge for modern medicine, which requires a detailed understanding of how dynamic molecular changes are integrated into the cellular context of nociceptive processing in spinal and brain circuits (Kuner, 2010). Molecular components of these pathways exhibit region- and cell-type-specific quantitative changes in chronic pain models (Samad et al, 2001; Zeilhofer, 2007; Sagar et al, 2012; Simonetti et al, 2013). Promoting endocannabinoid signaling or attenuating prostaglandin signaling are approaches generally considered to have analgesic potential (Zeilhofer & Brune, 2006; Jhaveri et al, 2007). Medical preparations from the cannabis plant stimulating cannabinoid (CB) receptors, and those from willow bark inhibiting prostaglandin-endoperoxidase synthases
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