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. 2010 Jul;150(1):17-21.
doi: 10.1016/j.pain.2010.02.011. Epub 2010 Apr 24.

Multiple PKCε-dependent mechanisms mediating mechanical hyperalgesia

Elizabeth K Joseph  1 , Jon D Levine
Affiliations

Multiple PKCε-dependent mechanisms mediating mechanical hyperalgesia

Elizabeth K Joseph et al. Pain. 2010 Jul.

Abstract

We have recently implicated mitochondrial mechanisms in models of neuropathic and inflammatory pain, in some of which a role of protein kinase Cepsilon (PKCepsilon) has also been implicated. Since mitochondria contain several proteins that are targets of PKCepsilon, we evaluated the role of mitochondrial mechanisms in mechanical hyperalgesia induced by proinflammatory cytokines that induce PKCepsilon-dependent nociceptor sensitization, and by a direct activator of PKCepsilon (psiepsilonRACK), in the rat. Prostaglandin E(2) (PGE(2))-induced hyperalgesia is short lived in naïve rats, while it is prolonged in psiepsilonRACK pre-treated rats, a phenomenon referred to as priming. Inhibitors of two closely related mitochondrial functions, electron transport (complexes I-V) and oxidative stress (reactive oxygen species), attenuated mechanical hyperalgesia induced by intradermal injection of psiepsilonRACK. In marked contrast, in a PKCepsilon-dependent form of mechanical hyperalgesia induced by prostaglandin E(2) (PGE(2)), inhibitors of mitochondrial function failed to attenuate hyperalgesia. These studies support the suggestion that at least two downstream signaling pathways can mediate the hyperalgesia induced by activating PKCepsilon.

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Figures

Figure. 1
Figure. 1. Time Course of ψεRACK, PGE2 and epinephrine hyperalgesia
A. Time course of the mechanical hyperalgesia induced by intradermal injection of prostaglandin E2 (PGE2, 100 ng), epinephrine (epi, 100 ng) and a PKCε activator (ψεRACK, 1 μg) on the dorsum of the hind paw. All three agents tested, produced a decrease in mechanical nociceptive threshold measured at 30 min (all p < 0.001, n = 6/group), the mechanical hyperalgesia was short lived (< 4 hr) in PGE2-and epinephrine- treated rats, but prolonged (> 72 hr) in ψεRACK-treated rats. B. Time course of the mechanical hyperalgesia induced by intradermal injection of prostaglandin E2 (PGE2, 100 ng) on the dorsum of the hind paw of rats treated 5 days previously with ψεRACK, 1 μg (i.e., primed). In ψεRACK primed rats, PGE 2 (100 ng)-induced peripheral mechanical hyperalgesia was significantly prolonged (> 24 hr, p < 0.001, n = 6).
Figure. 2
Figure. 2. Effect of Mitochondrial inhibitors on ψεRACK, PGE2 and epinephrine-induced hyperalgesia
A. Intradermal injection of inhibitors of mitochondrial electron complexes (I-V, each 5 μg) or ROS inhibitor α-lipoic acid (5 μg) together with ψεRACK (1 μg), significantly attenuated ψεRACK-induced hyperalgesia (all p < 0.001, n = 8/group). Non-selective caspase inhibitor, ZVAD-FMK and intracellular calcium mobilization blocker TMB-8 (both 5 μg, both p = ns; n = 8/group) did not affect ψεRACK-induced hyperalgesia. B. Intradermal injection of inhibitors of mitochondrial electron complexes (I-V), ROS inhibitor α-lipoic acid, non-selective caspase inhibitor, ZVAD-FMK and intracellular calcium mobilization blocker TMB-8 did not attenuate PGE2 (100 ng)-induced hyperalgesia (all p = ns; n = 8/group). C. Intradermal injection of inhibitors of mitochondrial electron complexes (I-V), non-selective caspase inhibitor, ZVAD-FMK and intracellular calcium mobilization blocker TMB-8 did not attenuate epinephrine (100 ng)-induced hyperalgesia (all p = ns; n = 8/group). However, ROS inhibitor α-lipoic acid significantly attenuated epinephrine-induced hyperalgesia (p < 0.001, n = 6).
Figure. 3
Figure. 3. Effect of Mitochondrial inhibitors on PGE2-induced hyperalgesia in primed (previously treated with ψεRACK) rats
A. Intradermal injection of mitochondrial electron complex inhibitors (I-V, each, 5 μg), ROS inhibitor α-lipoic acid, non-selective caspase inhibitor, ZVAD-FMK and intracellular calcium mobilization blocker TMB-8 (all 5 μg), did not attenuate PGE2 (100 ng)-induced hyperalgesia in ψεRACK-primed rats, when determined 30 min after the administration of PGE2 (all p = ns; n = 6/group). B. Intradermal injection of inhibitors of mitochondrial electron complexes (I-V), ROS inhibitor α-lipoic acid, non-selective caspase inhibitor, ZVAD-FMK and intracellular calcium mobilization blocker TMB-8 (all n = 6/group) did not attenuate PGE2 (100 ng)-induced hyperalgesia in ψεRACK-primed rats, when determined 4 hr after the administration of PGE2 (all p = ns; n = 6/group).
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