Elsevier

Neuroscience

Volume 160, Issue 2, 5 May 2009, Pages 501-507
Neuroscience

Pain Mechanism
Research Paper
Activation of Gi induces mechanical hyperalgesia poststress or inflammation

https://doi.org/10.1016/j.neuroscience.2009.03.001Get rights and content

Abstract

In studies of the role of primary afferent nociceptor plasticity in the transition from acute to chronic pain we recently reported that exposure to unpredictable sound stress or a prior inflammatory response induces long-term changes in the second messenger signaling pathway, in nociceptors, mediating inflammatory hyperalgesia; this change involves a switch from a Gs-cAMP-PKA to a Gi-PKCε signaling pathway. To more directly study the role of Gi in mechanical hyperalgesia we evaluated the nociceptive effect of the Gi activator, mastoparan. Intradermal injection of mastoparan in the rat hind paw induces dose-dependent (0.1 ng−1 μg) mechanical hyperalgesia. The highly selective inhibitors of Gi, pertussis toxin, and of protein kinase C epsilon (PKCε), PKCεV1-2, both markedly attenuate mastoparan-induced hyperalgesia in stressed rats but had no effect on mastoparan-induced hyperalgesia in unstressed rats. Similar effects were observed, at the site of nociceptive testing, after recovery from carrageenan-induced inflammation. These studies provide further confirmation for a switch to a Gi-activated and PKCε-dependent signaling pathway in primary mechanical hyperalgesia, induced by stress or inflammation.

Section snippets

Animals

Male (220–450 g) Sprague–Dawley rats (Charles River, Hollister, CA, USA) used in these experiments were housed in the Laboratory Animal Resource Center of the University of California, San Francisco, under a 12-h light/dark cycle. All experimental protocols were approved by the University of California, San Francisco, Institutional Animal Care and Use Committee, and conformed to NIH guidelines for the care and use of experimental animals. Effort was made to limit the numbers of animals used and

Results

While, for sound stress, we have previously shown a switch to Gi-as well as development of PKCε-dependence following recovery from prior inflammation we have not previously evaluated the switch to Gi dependence. In animals that had experienced prior inflammation at the site of nociceptive testing, PGE2 induced mechanical hyperalgesia was still unattenuated 4 h later (Fig. 1), a signature of hyperalgesic priming. This hyperalgesia was completely reversed by injection of PTx (100 ng/μl) at the

Discussion

In the present study we evaluated the role of the “inhibitory” heterotrimeric G protein, Gi, in inflammatory mediator-induced mechanical hyperalgesia in the rat. We have implicated a switch in signaling, from Gs to Gi, and onset of PKCε dependence for the second messenger pathway mediating PGE2-induced mechanical hyperalgesia, induced by prior stress (Khasar et al., 2008) or inflammation (Fig. 1; Aley et al., 2000). In the present study we evaluated whether activation of Gi was sufficient to

Conclusion

In conclusion, the present experiments confirm the role of a Gi-PKCε-mediated signaling pathway in primary afferent nociceptor sensitization and mechanical hyperalgesia associated with prior stress and inflammation, that may occur at or below the level of the Gi heterotrimeric G protein in the second messenger signaling pathway. It also provides support for a change in signaling pathway, a switch that is activated by stress or prior inflammation. Thus, Gi activity is sufficient for reproducing,

References (40)

Cited by (0)

View full text