Table 1.

Chronological studies of NPY receptor interventions on spinal cord physiology, pain, and itch

Model	Species	Sex	NPY Receptor Intervention	Outcome Measure	Key Results	Reference
Naïve	Rat	Male	Intrathecal (i.t.) NPY	Mean arterial blood pressure (MAP) and heart rate (HR)	NPY dose-dependently decreased MAP and HR in normotensive and hypotensive rats.	Chen et al., 1988
Naïve	Rat	Male	i.t. NPY	MAP and HR, multiunit activity recordings from exposed renal sympathetic nerve	NPY dose-dependently decreased MAP, slightly decreased HR, and decreased renal sympathetic nerve activity.	Chen et al., 1990
Naïve	Cat	Not Stated (NS)	Microinjection of NPY into the dorsal horn (DH)	Evoked release of immunoreactive substance P upon electrical stimulation of unmyelinated primary afferents of the tibial nerve	NPY reduced the evoked release of immunoreactive substance P.	Duggan et al., 1991
Naïve	Rat	Male	i.t. NPY	Heat: hotplate (HP) withdrawal (w/d) latency, Mechanical: pressure threshold	NPY dose-dependently increased the HP w/d latency but had no effect on mechanical pressure.	Hua et al., 1991
Naïve	Rat	Male	i.t. NPY, Y2 agonistic fragments, or Y1 agonist	MAP	NPY and Y2 agonistic fragments but not Y1 agonist dose-dependently decreased MAP.	Chen and Westfall, 1993
Neuropathic Pain: sciatic nerve transection	Rat	Female	i.t. NPY	Flexor reflex	NPY dose-dependently depressed flexor reflex in naïve and injured rats but the antinociceptive effect was stronger and longer lasting after nerve transection.	Xu et al., 1994
Neuropathic Pain: partial sciatic nerve ligation	Rat	NS	i.t. NPY, Y1 or Y2 agonists, or a nonselective NPY antagonist	Mechanical: pressure threshold	NPY or Y1 agonist but not Y2 agonist increased nerve injury-induced mechanical hypersensitivity. The nonselective NPY antagonist attenuated the nerve injury-induced hyperalgesia.	White, 1997
Naïve	Rat and Cat	Rat: Males; Cat: NS	None	DH release of immunoreactive NPY	Neither electrical stimulation of peripheral nerves nor noxious mechanical or heat stimulation changed the extensive spontaneous NPY release observed in the DH.	Mark et al., 1997
Neuropathic Pain: chronic constriction of the sciatic nerve	Rat	Male	None	DH release of immunoreactive NPY	CCI extended the zone of spontaneous ipsilateral release of NPY into the deep DH. Electrical stimulation of the injured nerves produced widespread NPY release.	Mark et al., 1998
Inflammatory Pain: hindpaw injection of carrageenan	Rat	Male and Female	i.t. NPY	Flexor reflex	NPY dose-dependently produced brief reflex facilitation at low doses and long-lasting depression at high doses in naïve and injured rats. The reflex facilitation was greater in carrageenan injected animals.	Xu et al., 1998
Neuropathic Pain: sciatic nerve transection	Rat	Female	i.t. Y1 or Y2 agonist	Flexor reflex	Y1 agonist dose-dependently produced reflex depression in naïve and injured rats. Y2 agonist did not produce reflex depression in naïve rats but dose-dependently produced reflex depression in sciatic nerve transected rats.	Xu et al., 1999
Neuropathic Pain: chronic constriction of the sciatic nerve	Rat	Male	None	DH release of immunoreactive NPY	Total conduction block of the injured nerve did not change spontaneous NPY release in the ipsilateral DH.	Colvin and Duggan, 2001
Inflammatory Pain: hindpaw injection of formalin, intraperitoneal injection of acetic acid or MgSO4; Neuropathic Pain: partial sciatic nerve ligation	Mouse	Male	Global knockout of Npy1r; i.t. NPY	Heat: HP w/d latency, tail flick latency; Mechanical: von Frey (vF) w/d threshold; Inflammatory Pain: number of events (lifting, shaking, licking and biting of the paw), number of abdominal stretches	Npy1r knockout increased sensitivity to heat and mechanical stimuli, hyperalgesia in the Phase I but not Phase II response to formalin, visceral hyperalgesia, and peripheral nerve injury-induced mechanical hypersensitivity. Npy1r knockout abolished the antinociceptive effect of NPY on heat hypersensitivity.	Naveilhan et al., 2001
Inflammatory Pain: hindpaw injection of carrageenan or CFA	Rat	Male	i.t. NPY or Y1 or Y2 antagonists	Heat: HP w/d latency, radiant heat w/d latency; Motor Coordination: latency to fall on an accelerating rotarod	NPY dose-dependently increased response latency to heat stimuli, inhibited carrageenan- and CFA-induced heat hypersensitivity, and did not alter motor coordination. The antinociceptive effects were abolished by a Y1 but not Y2 antagonist. A Y1 antagonist enhanced CFA-induced heat hypersensitivity.	Taiwo and Taylor, 2002
Naïve	Rat	NS	NPY or Y1 agonist on spinal cord (SC) slices	Electrophysiology: blind whole-cell patch-clamp recordings in voltage clamp, recording eEPSCs and eIPSCs, recording mEPSCs and mIPSCs, paired-pulse stimulation	NPY acts via Y1 to suppress inhibitory transmission by pre- and postsynaptic mechanisms. NPY acts via Y2 to suppress excitatory transmission exclusively by a presynaptic mechanism. NPY activates an inwardly rectifying K+ conductance in DH neurons.	Moran et al., 2004
Inflammatory Pain: hindpaw injection of formalin	Rat	Male	i.t. NPY or Y1 or Y2 antagonists	Inflammatory Pain: licking duration and the number of flinch events in the formalin assay; MAP and HR	NPY dose-dependently inhibited formalin-induced nocifensive responses that were partially blocked with a Y1 antagonist. NPY dose-dependently increased MAP that was prevented with a Y2 but not Y1 antagonist.	Mahinda et al., 2004
Naive	Rat	Male	NPY, Y1 agonist, or Y1 antagonist on SC slices	Capsaicin-evoked immunoreactive CGRP release from lumbar DH	NPY or Y1 agonist reduced CGRP exocytosis from central terminals of capsaicin sensitive afferent fibers and was partially blocked by a Y1 antagonist.	Gibbs et al., 2004
Naïve	Rat	Male	NPY, Y1 agonist, or Y1 antagonist on SC slices	Electrophysiology: whole-cell patch-clamp recordings in voltage clamp, recording mEPSCs and mIPSCs, recording dorsal root A- or C- fiber-evoked EPSCs	NPY or Y1 agonist induced a potassium-dependent outward current, membrane hyperpolarization, and a suppression of dorsal root stimulation-evoked action potentials. NPY-induced responses were blocked by a Y1 antagonist.	Miyakawa et al., 2005
Naïve	Mouse	Male	Global knockout of Npy1r	Mechanical: vF w/d threshold	Npy1r knockout mice demonstrated profound mechanical hypersensitivity.	Shi et al., 2006
Inflammatory Pain: hindpaw injection of CFA; Neuropathic Pain: partial sciatic nerve ligation	Mouse	Male	Global knockout of Npy1r; i.t. NPY or Y1 antagonist	Heat: HP w/d latency, radiant heat w/d latency; Mechanical: vF w/d threshold; Motor Coordination: latency to fall on an accelerating rotarod	Npy1r knockout produced heat hypersensitivity and longer lasting CFA-induced heat hyperalgesia. Npy1r knockout or a Y1 antagonist prevented the antinociceptive effect of NPY after CFA or partial sciatic nerve ligation. NPY and Y1 antagonist did not alter motor performance.	Kuphal et al., 2008
Inflammatory Pain: hindpaw injection of formalin; Neuropathic Pain: spared nerve injury (SNI, spared sural nerve)	Rat	Male	i.t. NPY or Y1 or Y2 antagonists	Inflammatory Pain: licking duration and the number of flinch events; Cold: acetone w/d duration; Mechanical: vF w/d threshold, tactile stimulus-evoked Fos expression in superficial DH	NPY reduced formalin-induced behaviors, dose-dependently reduced SNI-induced mechanical and cold hypersensitivities, and reduced both formalin- and SNI-induced tactile stimulus-evoked Fos expression. SNI-induced mechanical hypersensitivity and Fos expression were blocked by a Y1 or Y2 antagonist.	Intondi et al., 2008
Inflammatory Pain: hindpaw injection of formalin	Rat	Male and Female	i.t. NPY-saporin to selectively ablate Y1-INs	Heat: HP w/d latency and time licking and guarding hindpaws; Inflammatory Pain: time licking, lifting and biting, and number and time course of responses	NPY-saporin reduced SC but not DRG Y1 immunoreactivity. NPY-saporin elevated reflex w/d thresholds and reduced time spent licking/guarding paws to only low (44°C) heat. NPY-saporin reduced formalin-induced nocifensive behaviors.	Wiley et al., 2009
Inflammatory Pain: hindpaw injection of CFA, latent sensitization after CFA; Neuropathic Pain: SNI, CpxSx (spared tibial nerve), latent sensitization after CpxSx	Mouse	Male	Conditional doxycycline-induced global knockdown of NPY, or intrathecal Y1 or Y2 antagonists	Heat: HP w/d latency, radiant heat w/d latency; Cold: acetone w/d duration; Mechanical: vF w/d threshold; Motor Coordination: latency to fall on an accelerating rotarod; Ambulatory activity: exploration in an open field	NPY knockdown did not alter baseline sensory thresholds, motor coordination, or ambulatory activity but increased the intensity and duration of SNI-induced mechanical and cold hypersensitivity. Following the resolution of CFA- and CpxSx-induced behavioral hypersensitivities, NPY knockdown or Y1 or Y2 antagonists reinstated behavioral hypersensitivities. Y2 antagonist increased Fos and pERK in the DH 14 days after CFA.	Solway et al., 2011
Inflammatory Pain: hindpaw injection of CFA	Rat	Female	i.t. NPY-saporin to selectively ablate Y1-INs	Cold: 10°C cold plate (CP), thermal preference assay (two chamber 15°C vs. 45°C); Affective: feeding interference (overcome a 10°C floor plate to consume a sweet solution), and an escape task (climb onto a shelf to avoid a 10°C floor plate)	NPY-saporin reduced cold aversion on thermal preference and escape tasks, was analgesic to noxious heat on the escape task, and reduced CFA-induced hypersensitivity to cold temperatures experienced on the CP, thermal preference, feeding interference, and escape tasks.	Lemons and Wiley, 2012
Naïve	Rat	NS	NPY, Y1 or Y2 antagonists, or Y1 or Y2 agonists on SC slices	Electrophysiology: blind whole-cell patch-clamp recordings in voltage clamp, recording mEPSCs and mIPSCs; Morphological Categorization: post hoc	NPY or Y1 agonist induced a hyperpolarizing potassium conductance and outward current in primarily central- or radial-like neurons that was abolished by a Y1 but not Y2 antagonist. Y2 agonist had no effect on DH neurons. NPY moderately reduced the frequency of both mEPSCs and mIPSCs via Y1 and Y2.	Melnick, 2012
Inflammatory Pain: hindpaw plantar incision	Rat	Male	i.t. NPY, or Y1 or Y2 antagonists	Hindpaw guarding behavior; Mechanical: vF w/d threshold; Heat: radiant heat w/d latency	NPY reduced incision-induced guarding behavior and heat and mechanical hypersensitivity. The antinociceptive NPY effects were abolished with a Y1 but not Y2 antagonist.	Yalamuri et al., 2013
Inflammatory Pain: hindpaw injection of carrageenan or CFA	Rat and Mouse	Male	Superfusion of slices with Y1 agonist; i.t. NPY or Y1 agonist	NK1R internalization; Y1 agonist stimulated [35S]GTPγS binding; In vivo microdialysis of DH substance P release; Mechanical: vF w/d threshold, pin prick w/d duration; Cold: acetone w/d duration; Heat: radiant heat w/d latency	Y1 agonist decreased dorsal root stimulation-evoked NK1R internalization. CFA increased the affinity of coupling between Y1 and activated G-proteins, but its efficacy was reduced by roughly half. NPY reduced capsaicin-evoked substance P release in vivo. NPY or Y1 agonist inhibited CFA- and carrageenan-induced NK1R internalization and behavioral nociception.	Taylor et al., 2014
Inflammatory Pain: hindpaw injection of CFA; Mechanical Itch: touch-evoked itch test; Chemical Itch: intradermal pruritogens	Mouse	NS	Ablation or chemogenetic inhibition of SC NPY-Cre lineage interneurons	Mechanical: vF w/d threshold, responsiveness to light brush, pressure; Cold: acetone w/d duration, CP w/d latency; Heat: HP w/d latency, radiant heat w/d latency; Motor Coordination: latency to fall on accelerating rotarod; Mechanical Itch: alloknesis score from vF stimulation at nape; Chemical Itch: number of scratching and wiping behaviors and bouts	Ablation or inhibition of SC NPY-Cre lineage neurons induced spontaneous scratching behaviors and skin lesions, increased mechanical but not chemical itch, but did not alter cold, heat, or mechanical sensitivity, motor coordination, or CFA-induced mechanical hypersensitivity.	Bourane et al., 2015
Neuropathic Pain: chronic constriction injury (CCI)	Rat	Male	i.t. Y1 agonist	Mechanical: vF w/d threshold; Cold: acetone w/d duration	Y1 agonist dose-dependently reduced behavioral signs of CCI-induced mechanical and cold hypersensitivity.	Malet et al., 2017
Mechanical Itch: touch-evoked itch test; Chemical Itch: intradermal pruritogens	Mouse	NS	i.t. NPY, Y1 agonist, or Y1 antagonist	Mechanical Itch: scratch and shake episode frequency and duration from vF stimulation at nape; Chemical Itch: scratch and shake episode frequency and duration	Y1 agonist reduced shake episode frequency and duration induced by nape stimulation. NPY and Y1 agonist reduced the duration of compound 48/80- and histamine- but not chloroquine-induced scratching.	Gao et al., 2018
Bone Cancer Pain: intra-tibial infusion of MRMT1 - Luc2 cancer cells	Rat	Male and Female	i.t. NPY, or Y1 or Y2 antagonists	Limb use test and limb weight-bearing assay	NPY restored limb function and weight bearing and these antihyperalgesic effects were blocked by Y1 or Y2 antagonists.	Diaz-delCastillo et al., 2018
Inflammatory Pain: hindpaw plantar incision	Rat	Male	i.t. NPY	Mechanical: vF w/d threshold; hindpaw guarding behavior; Heat: radiant heat w/d latency	NPY reduced incision-induced hindpaw guarding and thermal hyperalgesia.	Gupta et al., 2018
Spontaneous Itch: non-evoked acute scratching behavior	Mouse	Male	i.t. Y1 agonist or Y1 or Y2 antagonists	Mechanical: vF w/d threshold; Heat: radiant heat w/d latency; Motor Coordination: latency to fall on an accelerating rotarod; Spontaneous Itch: number of scratching bouts	Y2 antagonist induced spontaneous pain-related scratching and mechanical but not thermal hypersensitivity. Y1 antagonist did not induce spontaneous scratching or mechanical or thermal hypersensitivity and alleviated Y2 antagonist-induced pain behaviors. Y2 antagonist but not Y1 agonist reduced motor coordination at high doses.	Chen et al., 2019
Inflammatory Pain: hindpaw injection of formalin or capsaicin; Spontaneous Itch: non-evoked acute scratching behavior; Mechanical Itch: touch-evoked itch test; Chemical Itch: intradermal pruritogens	Mouse	Male and Female	SC and hindbrain Npy1r knockout; Ablation of SC NPY-Cre lineage neurons; Ablation or chemogenetic activation and inhibition of SC Y1-Cre lineage interneurons	Mechanical: vF w/d threshold, responsiveness to light brush, pressure threshold, pin prick w/d duration; Heat: HP w/d latency, radiant heat w/d latency; Inflammatory Pain: time spent licking, flinching, and biting; Spontaneous Itch: number of spontaneous scratching bouts; Mechanical Itch: alloknesis score from vF stimulation at nape; Chemical Itch: scratching bouts, duration, and rate	Y1-Cre lineage neuron ablation prevented NPY-Cre lineage neuron ablation-induced itch, enhanced mechanical but not chemical itch, and reduced vF thresholds without affecting other mechanical, heat, or inflammatory pain behavioral responses. Activation of Y1-Cre lineage neurons reduced vF thresholds and increased mechanical and spontaneous itch. SC Npy1r knockout reduced vF thresholds but had no effect on other mechanical, heat, acute pain, or chemical pruritogen-induced behavioral responses.	Acton et al., 2019
Neuropathic Pain: SNI	Rat	Male	Y1 internalization in SC slices as an in situ measure of NPY release	Y1 internalization was quantified by visually counting Y1-INs in laminae I-II and classifying them as either with or without internalization; Mechanical: vF w/d threshold, and non-noxious- or noxious-evoked Y1 internalization.	NPY, capsaicin, NMDA, and high K+ induced Y1 internalization in DH neurons. Electrical stimulation of the DH frequency-dependently induced NPY release and was decreased by a Y1 antagonist. Dorsal root immersion in capsaicin induced NPY release and it was blocked by CNQX. Nerve injury increased Y1 internalization induced by DH stimulation and in vivo internalization induced by noxious and non-noxious stimuli.	Marvizon et al., 2019
Inflammatory Pain: Latent sensitization after intraplantar CFA	Mice	Male	i.t. Y1 antagonist	Mechanical: vF w/d threshold	Y1 antagonist reinstated mechanical hypersensitivity following the resolution of CFA-induced inflammation and this was prevented in AC1 knockout mice or with administration of a pharmacological blocker to the N-methyl-D-aspartate receptor (NMDAR), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), transient receptor potential cation channel A1 (TRPA1), channel V1 (TRPV1), or exchange protein activated by cAMP (Epac1 or Epac2).	Fu et al., 2019
Neuropathic Pain: SNI	Rat	Male	i.t. NPY, or NPY-saporin	Mechanical: vF w/d threshold, pressure threshold, pin prick w/d duration, tactile stimulus-evoked Fos expression in superficial DH; Cold: acetone w/d duration; Heat: HP w/d latency, radiant heat w/d latency; Motor Coordination: latency to fall on an accelerating rotarod; Ambulatory Activity: exploration in an open field	NPY-saporin dose-dependently attenuated the development of SNI-induced mechanical and cold hypersensitivity, but did not change normal mechanical or thermal thresholds, motor coordination, or locomotor activity. NPY reduced neuropathic mechanical hypersensitivity and light touch-evoked c-Fos expression in DH Y1-INs.	Nelson et al., 2019
Neuropathic Pain: Latent sensitization after CpxSx	Mouse	Male	Doxycycline-induced global knockdown of NPY, or intrathecal Y1 antagonist	Mechanical: vF w/d threshold; Cold: acetone w/d duration; Affective Pain: 3-chamber conditioned place preference and avoidance assay	Y1 antagonist or NPY knockdown induced conditioned place aversion (CPA). Y1 antagonist reinstated mechanical and cold hypersensitivity following the resolution of CpxSx-induced hypersensitivity and reinstatement and CPA were prevented in AC1 knockout mice or with an NMDA receptor antagonist, AC1 inhibitor, or TRPV1 or TRPA1 channel blockers.	Fu et al., 2020
Mechanical Itch: touch-evoked itch test; Chemical Itch: intradermal pruritogens; Atopic Dermatitis-like Itch: application of dust mite extract	Mouse	Male and Female	i.t. Y2 agonist or Y2 antagonist	Mechanical Itch: scratch and shake episode frequency and duration from vF stimulation at nape; Chemical Itch: scratch and shake episode frequency and duration; Atopic Dermatitis- like Itch: scratch and shake episode frequency and duration	Y2 agonist reduced the frequency and duration of compound 48/80-induced scratching and the duration of IL-31- and histamine-induced scratching. Y2 agonist did not reduce scratching induced by SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by vF at nape.	Ma et al., 2020
Inflammatory Pain: intra-articular injection of dilute formalin	Rat	Male	i.t. Y1 agonist, Y1 antagonist, or NPY-saporin	Mechanical: Paw Elevation Time (PET)-rats are placed on a revolving cylinder for 1min and scored for the total time that the hindpaw is not in contact with the cylinder surface	NPY-saporin and Y1 agonist reduced formalin-induced PET and conversely Y1 antagonist increased the PET.	Souza-Silva et al., 2020