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. 2014 Mar;15(3):312-20.
doi: 10.1016/j.jpain.2013.12.005. Epub 2014 Jan 7.

Second messengers mediating the expression of neuroplasticity in a model of chronic pain in the rat

Luiz F Ferrari  1 , Oliver Bogen  1 , Jon D Levine  2
Affiliations

Second messengers mediating the expression of neuroplasticity in a model of chronic pain in the rat

Luiz F Ferrari et al. J Pain. 2014 Mar.

Abstract

Hyperalgesic priming is a model of the transition from acute to chronic pain, in which previous activation of cell surface receptors or direct activation of protein kinase C epsilon markedly prolongs mechanical hyperalgesia induced by pronociceptive cytokines. We recently demonstrated a role of peripheral protein translation, alpha-calmodulin-dependent protein kinase II (αCaMKII) activation, and the ryanodine receptor in the induction of hyperalgesic priming. In the present study, we tested if they also mediate the prolonged phase of prostaglandin E2-induced hyperalgesia. We found that inhibition of αCaMKII and local protein translation eliminates the prolonged phase of prostaglandin E2 hyperalgesia. Although priming induced by receptor agonists or direct activation of protein kinase C epsilon occurs in male but not female rats, activation of αCaMKII and the ryanodine receptor also produces priming in females. As in males, the prolonged phase of prostaglandin E2-induced hyperalgesia in female rats is also protein kinase C epsilon-, αCaMKII-, and protein translation-dependent. In addition, in both male and female primed rats, the prolonged prostaglandin E2-induced hyperalgesia was significantly attenuated by inhibition of MEK/ERK. On the basis of these data, we suggest that the mechanisms previously shown to be involved in the induction of the neuroplastic state of hyperalgesic priming also mediate the prolongation of hyperalgesia.

Perspectives: The data provided by this study suggest that direct intervention on specific targets may help to alleviate the expression of chronic hyperalgesic conditions.

Keywords: Second messengers; hyperalgesic priming; mechanical hyperalgesia; rat; sensory neuron.

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Figures

Figure 1
Figure 1. The prolongation of PGE2-induced hyperalgesia in primed male rats is dependent on αCaMKII
Male rats that received intradermal injection of the PKCε activator ψεRACK (1 μg, panel A), activated αCaMKII (25 ng, panel B) or the ryanodine receptor agonist (1 μg, panel C) on the dorsum of the hind paw one (panels A and C) or two (panel B) weeks before were treated with intrathecal injection of ODN mismatch (clear bars) or antisense (black bars) for αCaMKII for 3 consecutive days. On the 4th day, vehicle or the αCaMKII inhibitor CaM2INtide (1 μg) was administered, 15 min prior to the injection of PGE2 (100 ng), at the same site. Mechanical nociceptive thresholds were evaluated 30 min and 4 h after PGE2, by the Randall-Selitto paw withdrawal test. We observed, in all cases, significant attenuation of the hyperalgesia induced by PGE2 at the 4th h in the groups pretreated with the antisense/CaM2INtide (panel A, F1,10 = 52.07, ***p < 0.0001; panel B, F1,10 = 68.83, ***p < 0.0001; panel C, F1,10 = 46.14, ***p < 0.0001), when compared to the mismatch/vehicle groups (two-way repeated measures ANOVA followed by Bonferroni post-test, n = 6 paws per group), indicating a role of αCaMKII in the prolongation of PGE2 hyperalgesia in the primed condition.
Figure 2
Figure 2. Prolonged phase of PGE2-induced hyperalgesia in male rats primed with ryanodine is dependent on local protein translation
Male rats received an intradermal injection of ryanodine (1 μg). One week later cordycepin (1 μg), rapamycin (1 μg), or vehicle was injected on the dorsum of the hind paw and, 15 min later, PGE2 (100 ng) was injected in the same site. Mechanical nociceptive thresholds were evaluated 30 min and 4 h after PGE2, by the Randall-Selitto paw withdrawal test. In all cases, the pretreatment with the protein translation inhibitor significantly attenuated the hyperalgesia induced by PGE2 at 4th h (***p < 0.001), when compared to the vehicle group (F2,15 = 85.11, ***p < 0.0001, two-way repeated measures ANOVA followed by Bonferroni post-test, n = 6 paws per group).
Figure 3
Figure 3. Prolonged phase of PGE2-induced hyperalgesia in rats with αCaMKII-induced hyperalgesic priming is dependent on PKCε, αCaMKII and local protein translation
Rats primed with intradermal injection of activated αCaMKII (25 ng) on the dorsum of the hind paw 2 weeks before received injection of PGE2 in the presence or absence of inhibitors of the seconds messengers PKCε (PKCε-I, panel A) or αCaMKII (ODN antisense or mismatch for αCaMKII and the αCaMKII inhibitor CaM2INtide, panel B), and the protein translation inhibitors cordycepin or rapamycin (panel C). Mechanical nociceptive thresholds were evaluated 30 min and 4 h after PGE2, by the Randall-Selitto paw withdrawal test. PGE2 was injected 5 min (panel A) or 15 min (panels B and C) after the inhibitors. We observed, in all cases, significant attenuation of the hyperalgesia induced by PGE2 at 4th h (***p < 0.001) in the groups treated with the inhibitors when compared to the ODN mismatch/vehicle groups (panel A, male rats: F1,10 = 27.36, p = 0.0004; female rats: F1,10 = 437.96, p < 0.0001; panel B, F1,10 = 57.90, p < 0.0001; panel C, F2,15 = 26.65, p < 0.0001, two-way repeated measures ANOVA followed by Bonferroni post-test, n = 6 paws per group), indicating a role of PKCε, αCaMKII and local protein translation in the prolongation of PGE2 hyperalgesia in the αCaMKII-induced hyperalgesic priming.
Figure 4
Figure 4. Prolonged phase of PGE2-induced hyperalgesia in rats previously treated with ryanodine is dependent on PKCε, αCaMKII and local protein translation
Rats primed with intradermal injection of ryanodine (1 μg) on the dorsum of the hind paw one week prior received intradermal injection of PGE2 on the dorsum of the hind paw in the presence or absence of inhibitors of the seconds messengers PKCε (PKCε-I, panel A) or αCaMKII (ODN antisense or mismatch for αCaMKII and the αCaMKII inhibitor CaM2INtide, panel B), and the protein translation inhibitors cordycepin or rapamycin (panel C). Mechanical nociceptive thresholds were evaluated 30 min and 4 h after PGE2, by the Randall-Selitto paw withdrawal test. PGE2 was injected 5 min (panel A) or 15 min (panels B and C) after the inhibitors. We observed, in all cases, significant attenuation of the hyperalgesia induced by PGE2 at the 4th h (***p < 0.001) in the groups treated with the inhibitors when compared to the vehicle groups (panel A, male rats: F1,10 = 36.03, p = 0.0001; female rats: F1,10 = 18.76, p < 0.0015; panel B, F1,10 = 56.01, p < 0.0001; panel C, F2,15 = 39.30, p < 0.0001, two-way repeated measures ANOVA followed by Bonferroni post-test, n = 6 paws per group), indicating a role of PKCε, αCaMKII and local protein translation in the prolongation of PGE2 hyperalgesia in the ryanodine-induced hyperalgesic priming.
Figure 5
Figure 5. Prolonged phase of PGE2-induced hyperalgesia is dependent on the MEK/ERK pathway in rats previously treated with activated αCaMKII or ryanodine
Different groups of rats that were treated with intradermal injection of activated αCaMKII (25 ng, panel A) or the ryanodine receptor agonist (1 μg, panel B) on the dorsum of the hind paw two or one week prior, respectively, received PGE2 (100 ng), at the same site, 5 min after the injection of vehicle or U0126 (1 μg). Mechanical nociceptive thresholds were evaluated 30 min and 4 h after PGE2, by the Randall-Selitto paw withdrawal test. We observed, in all cases, significant attenuation of the hyperalgesia induced by PGE2 at the 4th h (***p < 0.001) in the groups pretreated with the U0126 (panel A, male rats: F1,10 = 85.58, p < 0.0001; female rats: F1,10 = 20.37, p = 0.0011; panel B, male rats: F1,10 = 40.34, p < 0.0001; female rats: F1,10 = 25.35, p = 0.0005), when compared to the vehicle groups (two-way repeated measures ANOVA followed by Bonferroni post-test, n = 6 paws per group), indicating a role of the MEK/ERK pathway in the prolongation of PGE2 hyperalgesia in the primed condition.
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