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A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury.
Br J Pharmacol. 2004 Jan; 141(1):65-74.BJ

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+Show Affiliations

Department of Medical Laboratory Science and Technology, Karolinska Institutet, Stockholm, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14662726

Citation

Wu, Wei-Ping, et al. "A Nitric Oxide (NO)-releasing Derivative of Gabapentin, NCX 8001, Alleviates Neuropathic Pain-like Behavior After Spinal Cord and Peripheral Nerve Injury." British Journal of Pharmacology, vol. 141, no. 1, 2004, pp. 65-74.
Wu WP, Hao JX, Ongini E, et al. A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury. Br J Pharmacol. 2004;141(1):65-74.
Wu, W. P., Hao, J. X., Ongini, E., Impagnatiello, F., Presotto, C., Wiesenfeld-Hallin, Z., & Xu, X. J. (2004). A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury. British Journal of Pharmacology, 141(1), 65-74.
Wu WP, et al. A Nitric Oxide (NO)-releasing Derivative of Gabapentin, NCX 8001, Alleviates Neuropathic Pain-like Behavior After Spinal Cord and Peripheral Nerve Injury. Br J Pharmacol. 2004;141(1):65-74. PubMed PMID: 14662726.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury. AU - Wu,Wei-Ping, AU - Hao,Jing-Xia, AU - Ongini,Ennio, AU - Impagnatiello,Francesco, AU - Presotto,Cristina, AU - Wiesenfeld-Hallin,Zsuzsanna, AU - Xu,Xiao-Jun, Y1 - 2003/12/08/ PY - 2003/12/10/pubmed PY - 2005/1/26/medline PY - 2003/12/10/entrez SP - 65 EP - 74 JF - British journal of pharmacology JO - Br J Pharmacol VL - 141 IS - 1 N2 - 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/14662726/A_nitric_oxide__NO__releasing_derivative_of_gabapentin_NCX_8001_alleviates_neuropathic_pain_like_behavior_after_spinal_cord_and_peripheral_nerve_injury_ L2 - https://doi.org/10.1038/sj.bjp.0705596 DB - PRIME DP - Unbound Medicine ER -