Kappa opioids inhibit spinal output neurons to suppress itch.

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural basis for itch remains unclear. Here, we used two-photon Ca imaging of the dorsal horn to visualize neuronal populations that are activated by itch-inducing agents.

The functional and anatomical characterization of three spinal output pathways of the anterolateral tract.

The nature of spinal output pathways that convey nociceptive information to the brain has been the subject of controversy. Here, we provide anatomical, molecular, and functional characterizations of two distinct anterolateral pathways: one, ascending in the lateral spinal cord, triggers nociceptive behaviors, and the other one, ascending in the ventral spinal cord, when inhibited, leads to sensorimotor deficits. Moreover, the lateral pathway consists of at least two subtypes.

Identification of a convergent spinal neuron population that encodes itch.

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents.

Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp.

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity.

Translational research updates in female health anesthesiology: a narrative review.

Background And Objective: Females represent 49.6% of the global population and constitute a significant proportion of surgical patients and hospital admissions. Little is known about the bi-directional effects of sex and anesthetics or the impact of anesthetic interventions on long-term female health outcomes.

An identification key to the genera and species of Afrotropical Tetrigini (genera Paratettix, Leptacrydium, Hedotettix, Rectitettix nov. gen., and Alienitettix nov.gen.) with general remarks on the taxonomy of Tetrigini (Orthoptera, Tetrigidae).

The Afrotropical species hitherto considered to belong to the genera Paratettix Bolivar, 1887, Leptacrydium Chopard, 1950 and Hedotettix Bolivar, 1887 are reviewed, and two new genera, Alienitettix nov. gen. and Rectitettix nov.

Brainstem Modulation of Nociception by Periaqueductal Gray Neurons Expressing the μ-Opioid Receptor in Mice.

Background: Pharmacologic manipulations directed at the periaqueductal gray have demonstrated the importance of the μ-opioid receptor in modulating reflexive responses to nociception. The authors hypothesized that a supraspinal pathway centered on neurons in the periaqueductal gray containing the μ-opioid receptor could modulate nociceptive and itch behaviors.

Methods: The study used anatomical, optogenetic, and chemogenetic approaches in male and female mice to manipulate μ-opioid receptor neurons in the periaqueductal gray.

Cell type-specific dissection of sensory pathways involved in descending modulation.

Decades of research have suggested that stimulation of supraspinal structures, such as the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), inhibits nocifensive responses to noxious stimulation through a process known as descending modulation. Electrical stimulation and pharmacologic manipulations of the PAG and RVM identified transmitters and neuronal firing patterns that represented distinct cell types. Advances in mouse genetics, in vivo imaging, and circuit tracing methods, in addition to chemogenetic and optogenetic approaches, allowed the characterization of the cells and circuits involved in descending modulation in further detail.

The Delta-Opioid Receptor Bidirectionally Modulates Itch.

Opioid signaling has been shown to be critically important in the neuromodulation of sensory circuits in the superficial spinal cord. Agonists of the mu-opioid receptor (MOR) elicit itch, whereas agonists of the kappa-opioid receptor (KOR) have been shown to inhibit itch. Despite the clear roles of MOR and KOR for the modulation itch, whether the delta-opioid receptor (DOR) is involved in the regulation of itch remained unknown.

Inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla in mice.

The rostral ventromedial medulla (RVM) is important in descending modulation of spinal nociceptive transmission, but it is unclear if the RVM also modulates spinal pruriceptive transmission. RVM ON cells are activated by noxious algesic and pruritic stimuli and are pronociceptive. Many RVM-spinal projection neurons express the neurokinin-1 receptor (Tacr1), and ON-cells are excited by local administration of substance P (SP).

Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit.

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the rostral ventromedial medulla in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the rostral ventromedial medulla has never been achieved.

Evaluation of Therapies for Peripheral and Neuraxial Opioid-induced Pruritus based on Molecular and Cellular Discoveries.

Opioids are a mainstay of treatment for pain worldwide. Pruritus, a common side effect of opioids, is a patient dissatisfier that limits their use in many clinical settings. Both parenteral and neuraxial administration of opioids frequently evoke pruritus.

Morphine acts on spinal dynorphin neurons to cause itch through disinhibition.

Morphine-induced itch is a very common and debilitating side effect that occurs in laboring women who receive epidural analgesia and in patients who receive spinal morphine for relief of perioperative pain. Although antihistamines are still widely prescribed for the treatment of morphine-induced itch, their use is controversial because the cellular basis for morphine-induced itch remains unclear. Here, we used animal models and show that neuraxial morphine causes itch through neurons and not mast cells.

Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response.

The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation.

Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury.

Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; ) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain.

Peripheral Sensory Neurons Expressing Melanopsin Respond to Light.

The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve.

High-resolution characterization of a PACAP-EGFP transgenic mouse model for mapping PACAP-expressing neurons.

Pituitary adenylate cyclase-activating polypeptide (PACAP, gene name Adcyap1) regulates a wide variety of neurological and physiological functions, including metabolism and cognition, and plays roles in of multiple forms of stress. Because of its preferential expression in nerve fibers, it has often been difficult to trace and identify the endogenous sources of the peptide in specific populations of neurons. Here, we introduce a transgenic mouse line that harbors in its genome a bacterial artificial chromosome containing an enhanced green fluorescent protein (EGFP) expression cassette inserted upstream of the PACAP ATG translation initiation codon.

Novel Heterotypic Rox Sites for Combinatorial Dre Recombination Strategies.

Site-specific recombinases (SSRs) such as Cre are widely used in gene targeting and genetic approaches for cell labeling and manipulation. They mediate DNA strand exchange between two DNA molecules at dedicated recognition sites. Precise understanding of the Cre recombination mechanism, including the role of individual base pairs in its loxP target site, guided the generation of mutant lox sites that specifically recombine with themselves but not with the wild type loxP.