Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity(OIH)and analgesic tolerance.Among the different forms of OIH and tolerance,the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved.Here we demonstrated that the loss of peripheralμ-opioid receptors(MORs)or MOR-expressing neurons attenuated thermal tolerance,but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance.To confirm this result,we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons.Consistent with the behavioral results,peripheral MOR loss did not prevent the opening of Aβmechanical allodynia pathways in the spinal dorsal horn.Therefore,the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance.Future studies should focus more on central mechanisms.

Microglial Depletion does not Afect the Laterality of Mechanical Allodynia in Mice

Mechanical allodynia(MA),including punctate and dynamic forms,is a common and debilitating symptom suffered by millions of chronic pain patients.Some peripheral injuries result in the development of bilateral MA,while most injuries usually led to unilateral MA.To date,the control of such laterality remains poorly understood.Here,to study the role of microglia in the control of MA laterality,we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice.Surprisingly,the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA.Moreover,in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons.Consistent with behavioral results,microglial depletion did not prevent the opening of bilateral gates for Aβpathways in the superficial dorsal horn.This study challenges the role of microglia in the control of MA laterality in mice.Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.

Correction:Microglial Depletion does not Affect the Laterality of Mechanical Allodynia in Mice

The original version of this article unfortunately contained one error.The authors found that in the middle panel of Fig.2A,the example traces recorded from a contralateral dorsal horn neuron of the capsaicin-treated mouse were wrong,and the corrected Fig.2 was as follows.

Nuclear Factor I/A Controls A-fiber Nociceptor Development

Noxious mechanical information is transmitted through molecularly distinct nociceptors,with pinprickevoked sharp sensitivity via A-fiber nociceptors marked by developmental expression of the neuropeptide Y receptor 2(Npy2 r)and von Frey filament-evoked punctate pressure information via unmyelinated C fiber nociceptors marked by MrgprD.However,the molecular programs controlling their development are only beginning to be understood.Here we demonstrate that Npy2 r-expressing sensory neurons are in fact divided into two groups,based on transient or persistent Npy2 r expression.Npy2 r-transient neurons are myelinated,likely including A-fiber nociceptors,whereas Npy2 r-persistent ones belong to unmyelinated pruriceptors that co-express Nppb.We then showed that the transcription factors NFIA and Runx1 are necessary for the development of Npy2 r-transient A-fiber nociceptors and MrgprD^+C-fiber nociceptors,respectively.Behaviorally,mice with conditional knockout of Nfia,but not Runx1 showed a marked attenuation of pinprick-evoked nocifensive responses.Our studies therefore identify a transcription factor controlling the development of myelinated nociceptors.