Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits

Abstract

SummaryCellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur in vivo remains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics.

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

“…Here we used animal models of inflammatory and neuropathic pain to show that a single injection of compounds derived from botulinum toxin can silence pain-processing neurons in the spinal cord and decrease pain hypersensitivity. In two sets of experiments we targeted NK1R expressing neurons that relay pain-related information from the spinal cord to the brain and the MOR-expressing spinal cells that modulate activity of NK1R-expressing output neurons (10,30,35). We describe a long-term effect on mechanical pain sensitivity on both inflammatory and neuropathic pain states, following a single injection of the constructs and demonstrate in vivo receptor specificity.…”

“…Their analgesic properties are mostly mediated by the mu opioid receptor (MOR) (27) . In the dorsal horn MOR is expressed by interneurons and some primary afferents and by some projection neurons (28)(29)(30).…”

Opioids differentially modulate two synapses important for pain processing in the amygdala

“…These experiments do not allow us to determine whether there is co‐expression of the opioid receptors on individual BLA neurons. The dominance of μ‐receptor over δ‐receptor inhibition at the BLA–CeLC synapse is surprising in the light of the low expression of μ‐receptors and very high expression of δ‐receptors in the BLA using light‐level immunohistochemistry (Ding et al, ; Poulin et al, ; Wang et al, ). Although there have been some concerns about the specificity of opioid receptor antibodies, in particular those for δ‐receptors, the localization of high levels of δ‐receptors and low levels of μ‐receptors in the BLA is also found in δ‐receptors–GFP and μ‐receptor–mCherry mutant mice, which do not rely on opioid receptor antibodies (Wang et al, ).…”

“…The dominance of μ‐receptor over δ‐receptor inhibition at the BLA–CeLC synapse is surprising in the light of the low expression of μ‐receptors and very high expression of δ‐receptors in the BLA using light‐level immunohistochemistry (Ding et al, ; Poulin et al, ; Wang et al, ). Although there have been some concerns about the specificity of opioid receptor antibodies, in particular those for δ‐receptors, the localization of high levels of δ‐receptors and low levels of μ‐receptors in the BLA is also found in δ‐receptors–GFP and μ‐receptor–mCherry mutant mice, which do not rely on opioid receptor antibodies (Wang et al, ). BLA pyramidal neurons do express μ‐receptors, when studied using immuno‐electron microscopy (Zhang, Muller, & Mcdonald, ), and activation of μ‐receptors, but not of δ‐receptors, directly inhibits some lateral amygdala pyramidal neurons (Faber & Sah, ; Sugita & North, ).…”

“…In contrast, opioid receptor immunohistochemistry and mRNA levels in the BLA are overwhelmingly dominated by the very high levels of δ‐receptors (Le Merrer, Becker, Befort, & Kieffer, ; Mansour et al, ; Poulin, Chevalier, Laforest, & Drolet, ; Wang et al, ), while there are moderate levels of κ‐receptors (Unterwald et al, ) and low levels of μ‐receptors (Ding, Kaneko, Nomura, & Mizuno, ; Mansour et al, ; Wang et al, ). This high expression of δ‐receptors in the BLA and the high expression of δ‐receptors in the CeA (Wang et al, ) has resulted in the proposal that there is segregation of opioid receptors in distinct subnuclei of the amygdala and therefore distinct functions in amygdala circuits modulating pain affect (Wang et al, ). This profile of opioid receptor expression suggests that the “purely” nociceptive information coming from the PBeL will be inhibited by μ‐receptor agonists, such as morphine, but the polymodal information from the BLA will enter the CeLC unchecked.…”