19 Harley St, London, W1G 9QJ, UK

Stimulation of peripheral kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kgamma/AKT/nNOS/NO signaling pathway

BACKGROUND: In addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors (KORs) inhibits inflammatory pain. Moreover, peripheral mu-opioid receptor (MOR) activation are able to direct block PGE(2)-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE(2)-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated. RESULTS: Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE(2)-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kgamma/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kgamma null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kgamma ( congruent with 43%). CONCLUSIONS: The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kgamma/AKT signaling. This study extends a previously study of our group suggesting that PI3Kgamma/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons

Keywords : 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide,(trans)-Isomer,agonists,Analgesia,Animals,Class Ib Phosphatidylinositol 3-Kinase,complications,Dinoprostone,drug effects,Enzyme Activation,enzymology,Hyperalgesia,Inflammation,Male,metabolism,Mice,Mice,Inbred C57BL,Neurons,Nitric Oxide,Nitric Oxide Synthase Type I,Nociception,Pain,pathology,Peripheral Nervous System,pharmacology,Proto-Oncogene Proteins c-akt,Rats,Receptors,Opioid,kappa,Signal Transduction,Universities,, Peripheral,Kappa,Opioid,Receptors, bupa back pain

Date of Publication : 2012 Feb 8

Authors : Cunha TM;Souza GR;Domingues AC;Carreira EU;Lotufo CM;Funez MI;Verri WA;Cunha FQ;Ferreira SH;

Organisation : Department of Pharmacology, School of Medicine of Ribeirao Preto University of Sao Paulo, Av, Bandeirantes, 3900, 14049-900, Ribeirao Preto SP, Brazil. thicunha@usp.br

Journal of Publication : Mol Pain

Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/22316281

The London Spine Unit : Harley Street UK. Specialists in Cutting Edge Technologies for Spinal Surgery

Make an Appointment 

Trustpilot Reviews
Doctify Reviews
Top Doctor Reviews

Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3K?/AKT/nNOS/NO signaling pathway | Neck pain from sitting at computer

What our patients say ...

Consultant Spine Surgeon
Consultant Spine Surgeon
Consultant Spine Surgeon

This surgical technique consists of a percutaneous approach for the treatment of small to medium size hernias of the intervertebral disc by laser energy. The main objective is to reduce the intradiscal pressure in the nucleus pulposus

Laser Disc Surgery can be performed under local anaesthetic as a day case at our centre on the prestigious Harley Street.
What is London spine unit and How it Works

The London Spine Unit was established in 2005 and has successfully treated over 5000 patients. All conditions are treated.

treatment of all spinal disorders

The London Spine Unit specialises in Minimally Invasive Treatments allowing rapid recovery and return to normal function

Trusted by patients worldwide

The London Spine Unit provides the highest quality care to all patients and has VIP services for those seeking exceptional services

If you have any emergency Doctor’s need, simply call our 24 hour emergency

Your personal case manager will ensure that you receive the best possible care.

Call Now 

+44 844 589 2020
+44 203 973 8810