title: α-conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement.
abstract: Neuropathic pain affects millions of people worldwide, causing substantial disability and greatly impairing quality of life. Commonly used analgesics or antihyperalgesic compounds are generally characterized by limited therapeutic outcomes. Thus, there is a compelling need for novel therapeutic strategies able to prevent nervous tissue alterations responsible for chronic pain. The α9α10 nicotinic acetylcholine receptor antagonist α-conotoxin RgIA (RgIA), a peptide isolated from the venom of a carnivorous cone snail, induces relief in both acute and chronic pain models. To evaluate potential disease-modifying effects of RgIA, the compound was given to rats following chronic constriction injury (CCI) of the sciatic nerve. Two or 10 nmol RgIA injected intramuscularly once a day for 14 days reduced the painful response to suprathreshold stimulation, increased pain threshold to nonnoxious stimuli, and normalized alterations in hind limb weight bearing. Histological analysis of the sciatic nerve revealed that RgIA prevented CCI-induced decreases of axonal compactness and diameter, loss of myelin sheath, and decreases in the fiber number. Moreover, RgIA significantly reduced edema and inflammatory infiltrate, including a decrease of CD86(+) macrophages. In L4-L5 dorsal root ganglia, RgIA prevented morphometric changes and reduced the inflammatory infiltrate consistent with a disease-modifying effect. In the dorsal horn of the spinal cord, RgIA prevented CCI-induced activation of microglia and astrocytes. These data suggest that RgIA-like compounds may represent a novel class of therapeutics for neuropathic pain that protects peripheral nervous tissues as well as prevents central maladaptive plasticity by inhibiting glial cell activation.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence, Italy. Electronic address: lorenzo.mannelli@unifi.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cinci
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanardelli
authors.affiliation: Department of Experimental and Clinical Medicine - DMSC - Anatomy and Histology Section, University of Florence, Florence, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pacini
authors.affiliation: George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, USA; Department of Biology, University of Utah, Salt Lake City, UT, USA; Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D020916:Conotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D005727:Ganglia, Spinal / Q000187:drug effects; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D059348:Peripheral Nerve Injuries / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D000700:Analgesics; D020916:Conotoxins; C510079:conotoxin alpha-RgIA, Conus regius
keywords: Chronic constriction injury; Neuropathic pain; Neuroprotection; α-Conotoxin RgIA