title: Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain.
abstract: A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of dorsal root ganglion or spinal neuropathic markers after SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (ie, OFF) and excitatory (ie, ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α(2) adrenergic receptors precipitated allodynia in previously nonallodynic HZ rats with SNL. All rats showed an equivalent first-phase formalin responses. However, HZ rats had reduced second-phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA Department of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z4 Integrative Neuroscience Section, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA Medtronic Inc., Minneapolis, MN 55432, USA Ernest Gallo Clinic & Research Center, University of California, San Francisco, Emeryville, CA 94608, USA.
authors: Milena
authors: M
authors: De Felice
authors: Raul
authors: R
authors: Sanoja
authors: Ruizhong
authors: R
authors: Wang
authors: Louis
authors: L
authors: Vera-Portocarrero
authors: Janice
authors: J
authors: Oyarzo
authors: Tamara
authors: T
authors: King
authors: Michael H
authors: MH
authors: Ossipov
authors: Todd W
authors: TW
authors: Vanderah
authors: Josephine
authors: J
authors: Lai
authors: Gregory O
authors: GO
authors: Dussor
authors: Howard L
authors: HL
authors: Fields
authors: Theodore J
authors: TJ
authors: Price
authors: Frank
authors: F
authors: Porreca
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000503:physiopathology*; D004195:Disease Models, Animal; D004525:Efferent Pathways / Q000187:drug effects / Q000502:physiology; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009437:Neuralgia / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology / Q000502:physiology*