Stimulation of Peripheral Kappa Opioid Receptors Inhibits Inflammatory Hyperalgesia via Activation of the PI3Kγ/AKT/nNOS/NO Signaling Pathway

Abstract

BackgroundIn 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 μ-opioid receptor (MOR) activation are able to direct block PGE2-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 PGE2-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated.ResultsLocal (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE2-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 PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ 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 PI3Kγ (≅ 43%).ConclusionsThe 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 PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.

Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: Potential roles in acute inflammatory pain

“…antagonism of the γ-isoform resulted in a more profound and prolonged anti-allodynic effect. These data conflict with those of Ferreira and colleagues [13; 14] who found that morphine’s peripheral anti-hyperalgesia actions are dependent on intact PI3Kγ in the paw. This discrepancy might, in part, be attributed to many differences in protocols, because the two studies used different antagonists with different relative γ/α selectivities, however, Ferreira’s group observed a similar loss of morphine efficacy following the use of PI3Kγ antisense, which strengthens their observation.…”

Involvement of Protein Kinase B/Akt in Analgesic Effect of Dexmedetomidine on Neuropathic Pain

“…Furthermore, Xu et al [10] found that inhibition of PKB/Akt activation in the spinal cord decreased abnormal pain behaviors, suggesting that PKB/Akt signal pathway activation might contribute to the development of neuropathic pain. However, the results from Ferreira's laboratory showed that blockade of PI3K/Akt pathway prevented opioids-induced antinociception [7,8]. Similarly, we revealed that intrathecal dexmedetomidine upregulated spinal pAkt expression and alleviated mechanical allodynia in CCI rats, suggesting that PKB/Akt signaling activation might mediate dexmedetomidine-induced antiallodynia.…”

“…Recently, it has been found that stimulation of the PI3K/Akt signaling pathway by opioid receptors directly blocked inflammatory hyperalgesia [7,8]. Moreover, a previous report showed that dexmedetomidine likely activated PKB/Akt signaling via a 2 adrenoceptors to reduce cell death and to provide renoprotection, suggesting a link between a 2 adrenoceptors and PKB/Akt pathway [9].…”

Observing Anti-inflammatory and Anti-nociceptive Activities of Glycyrrhizin Through Regulating COX-2 and Pro-inflammatory Cytokines Expressions in Mice

“…Some studies demonstrated that inflammatory cytokines (such as TNF-α, IL-6, and iNOS) and inducible enzymes such as COX-2 are both induced through the NF-κB pathway [30,31]. Excess amount of NO plays an important role in the aggravation of inflammatory diseases; thus, NO production and iNOS expression are considered pharmacologic targets for antiinflammatory drugs.…”