title: Neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues.
abstract: Nociceptive information is modulated by a large number of endogenous signaling agents that change over the course of recovery from injury. This plasticity makes understanding regulatory mechanisms involved in descending inhibition of pain scientifically and clinically important. Neurons that synthesize the neuropeptide TIP39 project to many areas that modulate nociceptive information. These areas are enriched in its receptor, the parathyroid hormone 2 receptor (PTH2R). We previously found that TIP39 affects several acute nociceptive responses, leading us to now investigate its potential role in chronic pain. Following nerve injury, both PTH2R and TIP39 knockout mice developed less tactile and thermal hypersensitivity than controls and returned to baseline sensory thresholds faster. Effects of hindpaw inflammatory injury were similarly decreased in knockout mice. Blockade of α-2 adrenergic receptors increased the tactile and thermal sensitivity of apparently recovered knockout mice, returning it to levels of neuropathic controls. Mice with locus coeruleus (LC) area injection of lentivirus encoding a secreted PTH2R antagonist had a rapid, α-2 reversible, apparent recovery from neuropathic injury similar to the knockout mice. Ablation of LC area glutamatergic neurons led to local PTH2R-ir loss, and barley lectin was transferred from local glutamatergic neurons to GABA interneurons that surround the LC. These results suggest that TIP39 signaling modulates sensory thresholds via effects on glutamatergic transmission to brainstem GABAergic interneurons that innervate noradrenergic neurons. TIP39's normal role may be to inhibit release of hypoalgesic amounts of norepinephrine during chronic pain. The neuropeptide may help maintain central sensitization, which could serve to enhance guarding behavior.
authors.affiliation: Section on Fundamental Neuroscience, National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Dimitrov
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kuo
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.forename: Ted B
authors.initials: TB
authors.lastname: Usdin
mesh_terms: D000818:Animals; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006614:Hindlimb / Q000473:pathology / Q000503:physiopathology; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D008125:Locus Coeruleus / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009437:Neuralgia / Q000235:genetics / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010147:Pain Measurement; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D051273:Glucose Transporter Type 2; D009479:Neuropeptides; D044183:Receptor, Parathyroid Hormone, Type 2; D018341:Receptors, Adrenergic, alpha-2; C495682:Slc2a2 protein, mouse; C400136:tuberoinfundibular peptide 39; D018698:Glutamic Acid
keywords: Freund's adjuvant; allodynia; partial sciatic nerve ligation; supraspinal pain