title: A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury.
abstract: 1. Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. 2. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. 3. NCX8001 (1-30 microm) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC(50)=5.6 microm) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC(50)=1.4 microm). 4. NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNFalpha) from stimulated RAW264.7 cells. 5. NCX8001 (28-280 micromol x kg(-1), i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170-580 micromol x kg(-1), i.p.) resulted less effective and elicited marked side effects. 6. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. 7. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain.
authors.affiliation: Department of Medical Laboratory Science and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Wu
authors.forename: Jing-Xia
authors.initials: JX
authors.lastname: Hao
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: Francesco
authors.initials: F
authors.lastname: Impagnatiello
authors.forename: Cristina
authors.initials: C
authors.lastname: Presotto
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Wiesenfeld-Hallin
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Xu
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000588:Amines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000096:biosynthesis / Q000737:chemistry; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D000077206:Gabapentin; D006801:Humans; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000009:adverse effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009566:Nitrates / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism*; D016716:PC12 Cells; D010146:Pain / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000187:drug effects* / Q000503:physiopathology; D011817:Rabbits; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C495330:1-(aminomethyl)cyclohexaneacetic acid 3-(nitrooxymethyl)phenyl ester; D000085:Acetates; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D003510:Cyclohexanes; D008070:Lipopolysaccharides; D009566:Nitrates; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D006152:Cyclic GMP