Opioid pain medications cause detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia, and drive dose escalation. The cell-types and receptors on which opioids act to initiate these maladaptive processes remain disputed, preventing the development of therapies to maximize and sustain opioid analgesic efficacy. Here we establish that mu-opioid receptors (MOR) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA-sequencing and histological analysis revealed that MOR is expressed by nociceptors, but not by spinal microglia. Deletion of MOR specifically in nociceptors eliminated morphine tolerance, OIH, and pronociceptive synaptic long-term potentiation, without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, is sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support combining opioid agonists with peripheral MOR antagonists to limit analgesic tolerance and OIH.

One area that has emerged as a promising therapeutic target for the treatment and prevention of chronic pain and opioid tolerance/hyperalgesia is the modulation of the central nervous system (CNS) immunological response that ensues following injury or opioid administration. Broadly defined, central neuroimmune activation involves the activation of cells that interface with the peripheral nervous system and blood. Activation of these cells, as well as parenchymal microglia and astrocytes by injury, opioids, and other stressors, leads to subsequent production of cytokines, cellular adhesion molecules, chemokines, and the expression of surface antigens that enhance a CNS immune cascade. This response can lead to the production of numerous pain mediators that can sensitize and lower the threshold of neuronal firing: the pathologic correlate to central sensitization and chronic pain states. CNS innate immunity and Toll-like receptors, in particular, may be vital players in this orchestrated immune response and may hold the answers to what initiates this complex cascade. The challenge remains in the careful perturbation of injury/opioid-induced neuroimmune activation to down-regulate this process without inhibiting beneficial CNS autoimmunity that subserves neuronal protection following injury.

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.

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Objective-Several neurologic disorders are treated with deep brain stimulation; however, the mechanism underlying its ability to abolish oscillatory phenomena associated with diseases as diverse as Parkinson's and epilepsy remain largely unknown. In this study we sought to investigate the role of specific neurotransmitters in deep brain stimulation (DBS) and determine the role of non-neuronal cells in its mechanism of action.Methods-We used the ferret thalamic slice preparation in vitro, which exhibits spontaneous spindle oscillations, in order to determine the effect of high-frequency stimulation on neurotransmitter release. We then performed experiments using an in vitro astrocyte culture to investigate the role of glial transmitter release in HFS-mediated abolishment of spindle oscillations.Results-In this series of experiments we demonstrated that glutamate and adenosine release in ferret slices was able to abolish spontaneous spindle oscillations. The glutamate release was still evoked in the presence of the Na + channel blocker tetrodotoxin (TTX), but was eliminated with the vesicular H + -ATPase inhibitor, bafilomycin, and the calcium chelator, BAPTA-AM. Furthermore, electrical stimulation of purified primary astrocytic cultures was able to evoke intracellular calcium transients and glutamate release, and bath application of BAPTA-AM inhibited glutamate release in this setting.Conclusion-These results suggest that vesicular astrocytic neurotransmitter release may be an important mechanism by which DBS is able to achieve clinical benefits.

SUMMARY Changes in basal ganglia plasticity at the corticostriatal and thalamostriatal level are required for motor learning. Endocannabinoid-dependent long-term depression (eCB-LTD) is known to be a dominant form of synaptic plasticity expressed at these glutamatergic inputs; however, whether eCB-LTD can be induced at all inputs on all striatal neurons is still debatable. Using region-specific Cre mouse lines combined with optogenetic techniques, we directly investigated and distinguished between corticostriatal and thalamostriatal projections. We found that eCB-LTD was successfully induced at corticostriatal synapses, independent of postsynaptic striatal spiny projection neuron (SPN) subtype. Conversely, eCB-LTD was only nominally present at thalamostriatal synapses. This dichotomy was attributable to the minimal expression of cannabinoid type-1 (CB1) receptors on thalamostriatal terminals. Furthermore, co-activation of dopamine receptors on SPNs during LTD induction re-established SPN subtype-dependent eCB-LTD. Altogether, our findings lay the groundwork for understanding corticostriatal and thalamostriatal synaptic plasticity and for striatal eCB-LTD in motor learning.

The original version of this article omitted two citations. These papers provide a seminal description of retinal waves (Meister et al., 1991) and their effects on retinogeniculate patterning (Penn et al., 1998). These citations have been added, and the article has now been corrected online.

SUMMARY Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated nociceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanoreceptors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cutaneous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity.