The overall goal of this proposal is to determine that peripheral somatostatin (SST) receptor activation is critical in controlling nociceptor excitability, reducing peripheral sensitization and promoting analgesia. SST, a peptide found in primary afferents, or its long lasting agonist Octreotide, has been shown to prevent peripheral sensitization. Peripheral sensitization of nociceptors is a key element that not only underlies primary hyperalgesia in the peripheral but also contributes to central sensitization. The proposal explores the use of an SST agonist in the periphery to reduce peripheral sensitization in inflammatory pain. The hypothesis is that peripheral SST receptors play a critical role in modulating nociceptor sensitization in normal and inflamed skin.
The aims are to show that 1) SST receptors are on peripheral afferents and increase during inflammation; 2) peripheral SST receptor activation reduces the nociceptive responses and sensitization of nociceptors during inflammation; 3) peripheral SST receptor activation inhibits nociceptive behavioral responses in normal and inflamed animals; 4) SST receptors exert a tonic inhibitory influence over peripheral nociceptors; 5) SST agonists acts through non-opioid mechanisms; 6) that peripheral administration of SST agonists does not produce neurotoxicity; 7) endogenous SST can be released to help the body cope with inflammatory pain. Preliminary data suggest that SST2a receptors are localized on nociceptors in the glabrous skin in the rat. Activation of these receptors with Octreotide attenuates bradykinin-induced sensitization of nociceptors using an in vitro skin-nerve preparation and intraplantar injection of Octreotide attenuates formalin- and complete Freund's adjuvant-inducted nociceptor behaviors. The preliminary data suggests that SST exerts a tonic inhibitory control over peripheral nociceptors and that endogenous SST is released to help the body cope with inflammatory pain. Peripheral SST receptors offer novel targets for nociceptor modulation and are likely targets for further development of non-opioid therapies to aid in reducing the pain and long-term deleterious changes that can accompany inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040700-04
Application #
6696956
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (01))
Program Officer
Porter, Linda L
Project Start
2000-12-20
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2005-11-30
Support Year
4
Fiscal Year
2004
Total Cost
$360,250
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Carlton, Susan M; Du, Junhui; Zhou, Shengtai (2009) Group II metabotropic glutamate receptor activation on peripheral nociceptors modulates TRPV1 function. Brain Res 1248:86-95
Du, J; Zhou, S; Carlton, S M (2008) Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states. Neuroscience 154:754-66
Ji, G; Zhou, S; Carlton, S M (2008) Intact Adelta-fibers up-regulate transient receptor potential A1 and contribute to cold hypersensitivity in neuropathic rats. Neuroscience 154:1054-66
Ji, G; Zhou, S; Kochukov, M Y et al. (2007) Plasticity in intact A delta- and C-fibers contributes to cold hypersensitivity in neuropathic rats. Neuroscience 150:182-93
Carlton, Susan M; Hargett, Gregory L (2007) Colocalization of metabotropic glutamate receptors in rat dorsal root ganglion cells. J Comp Neurol 501:780-9
Jimenez-Andrade, Juan Miguel; Lundstrom, Linda; Sollenberg, Ulla E et al. (2006) Activation of peripheral galanin receptors: differential effects on nociception. Pharmacol Biochem Behav 85:273-80
Du, J; Zhou, S; Carlton, S M (2006) Kainate-induced excitation and sensitization of nociceptors in normal and inflamed rat glabrous skin. Neuroscience 137:999-1013
Jimenez-Andrade, Juan Miguel; Zhou, Shengtai; Yamani, Ammar et al. (2005) Mechanism by which peripheral galanin increases acute inflammatory pain. Brain Res 1056:113-7
Coggeshall, Richard E; Tate, Simon; Carlton, Susan M (2004) Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats. Neurosci Lett 355:45-8
Jimenez-Andrade, Juan Miguel; Zhou, Shengtai; Du, Junhui et al. (2004) Pro-nociceptive role of peripheral galanin in inflammatory pain. Pain 110:10-21

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