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. 2015 Jan 14;35(2):495-507.
doi: 10.1523/JNEUROSCI.5147-13.2015.

Accounting for the delay in the transition from acute to chronic pain: axonal and nuclear mechanisms

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

Accounting for the delay in the transition from acute to chronic pain: axonal and nuclear mechanisms

Luiz F Ferrari et al. J Neurosci. .

Abstract

Acute insults produce hyperalgesic priming, a neuroplastic change in nociceptors that markedly prolongs inflammatory mediator-induced hyperalgesia. After an acute initiating insult, there is a 72 h delay to the onset of priming, for which the underlying mechanism is unknown. We hypothesized that the delay is due to the time required for a signal to travel from the peripheral terminal to the cell body followed by a return signal to the peripheral terminal. We report that when an inducer of hyperalgesic priming (monocyte chemotactic protein 1) is administered at the spinal cord of Sprague Dawley rats, priming is detected at the peripheral terminal with a delay significantly shorter than when applied peripherally. Spinally induced priming is detected not only when prostaglandin E2 (PGE2) is presented to the peripheral nociceptor terminals, but also when it is presented intrathecally to the central terminals in the spinal cord. Furthermore, when an inducer of priming is administered in the paw, priming can be detected in spinal cord (as prolonged hyperalgesia induced by intrathecal PGE2), but only when the mechanical stimulus is presented to the paw on the side where the priming inducer was administered. Both spinally and peripherally induced priming is prevented by intrathecal oligodeoxynucleotide antisense to the nuclear transcription factor CREB mRNA. Finally, the inhibitor of protein translation reversed hyperalgesic priming only when injected at the site where PGE2 was administered, suggesting that the signal transmitted from the cell body to the peripheral terminal is not a newly translated protein, but possibly a newly expressed mRNA.

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Figures

Figure 1.
Figure 1.
Spinal administration of TNFα, IL-6, NGF, or MCP-1 induces hyperalgesic priming. Different groups of rats received a 20 μl spinal injection of TNFα (C, 20 ng/μl), IL-6 (D, 1 ng/μl), NGF (E, 150 ng/μl), or MCP-1 (F, 20 ng/μl). All four mediators induced mechanical hyperalgesia. Ninety-six hours after injection, the mechanical nociceptive paw withdrawal threshold, evaluated by the Randall-Sellitto method, had returned to values not statistically different from preinjection values (paired Student's t test). Average paw withdrawal threshold values before and 96 h after the spinal injections were as follows: TNFα, 121.0 ± 2.1 and 118.3 ± 2.2 g, respectively (t(5) = 1.061; p = 0.3370); NGF, 123.3 ± 1.6 and 120.0 ± 1.5 g, respectively (t(5) = 2.500; p = 0.0545); IL-6, 123.3 ± 1.7 and 123.0 ± 2.1 g, respectively (t(5) = 0.2548; p = 0.8090); and MCP-1, 123.0 ± 1.7 g and 121.3 ± 2.0 g, respectively (t(11) = 1.131; p = 0.2821). PGE2 (100 ng) was then injected intradermally into the dorsum of the hindpaw, and the mechanical threshold evaluated 30 min and 4 h later. In all cases, PGE2-induced hyperalgesia remained unatennuated at the fourth hour after injection [nonsignificant (NS) in all cases: C, p = 0.6505; D, p = 0.7423; E, p = 0.1592; F, p = 0.1098; two-way repeated-measures ANOVA followed by Bonferroni post-test], demonstrating the presence of hyperalgesic priming (C–E, N = 3 rats, 6 paws per group; F, N = 6 rats, 12 paws per group). A, In the schematic, the red arrow represents the signal triggered by the spinal injection (1, red syringe) of the priming agents (TNFα, IL-6, NGF, or MCP-1), in the central terminal of the nociceptor, directed to the cell body. A signal for the neuroplastic change then spreads to the peripheral terminal in the skin (blue arrow), where the presence of hyperalgesic priming can be detected by evaluating the hyperalgesia induced by the injection of PGE2 (2, blue syringe). B, In control experiments, the hyperalgesia induced by PGE2 in naive rats (nonprimed), no longer present at the fourth hour after injection, is shown (***p < 0.0001, when compared with the hyperalgesia at 30 min).
Figure 2.
Figure 2.
Time course of development of hyperalgesic priming induced by intradermal (paw) or intrathecal spinal injection of MCP-1. Different groups of rats received injections of MCP-1 intradermally into the dorsum of the hindpaw (100 ng; A) or intrathecally in the spinal cord (20 ng/μl, 20 μl; B). PGE2 (100 ng) was injected into the dorsum of the hindpaw 24 h (left panels), 48 h (middle panels), or 72 h (right panels) later, and, the mechanical hyperalgesia, evaluated by the Randall-Selitto paw withdrawal test, 30 min and 4 h later. Average paw withdrawal thresholds before, and 24, 48, and 72 h after intradermal injection of MCP-1 (A) were as follows: 120.0 ± 1.4 and 107.5 ± 1.8 g, respectively (after 24 h, t(11) = 10.56; p < 0.0001; paired Student's t test); 119.6 ± 1.4 and 116.1 ± 0.9 g, respectively (after 48 h, t(11) = 2.782; p = 0.1790, NS); and 118.6 ± 1.1 and 114.1 ± 1.3 g, respectively (after 72 h, t(11) = 2.279; p = 0.4360, NS). For the groups treated with intrathecal injection of MCP-1 (B), the average paw withdrawal thresholds before, and 24, 48, and 72 h after injections were as follows: 120.1 ± 1.5 and 98.0 ± 2.0 g, respectively (after 24 h, t(11) = 8.071; p < 0.0001; paired Student's t test); 116.8 ± 2.1 and 110.5 ± 1.2 g, respectively (after 48 h, t(11) = 2.588; p = 0.2502, NS); and 120.3 ± 1.5 and 116.6 ± 1.9 g, respectively (after 72 h, t(11) = 1.910; p = 0.0826, NS). In the groups treated with MCP-1 into the dorsum of the hindpaw (A), hyperalgesic priming was not established until 72 h [24 and 48 h panels: ***p < 0.0001 when comparing the PGE2-induced hyperalgesia at 30 min and 4 h; 72 h panel: p = 0.9404 (NS); two-way repeated-measures ANOVA followed by Bonferroni post-test, N = 6 rats (12 paws) per group]. On the other hand, in the group treated with spinal MCP-1 (B), although the injection of PGE2 on the next day induced short-lasting hyperalgesia, it was no longer present at the fourth hour time point (***p < 0.0001 when comparing both time points); when PGE2 was injected 48 or 72 h after spinal MCP-1, the hyperalgesia remained statistically unattenuated at the fourth hour [NS in both cases: 48 h panel, p = 0.1864; 72 h panel, p = 0.3635; two-way repeated-measures ANOVA followed by Bonferroni post-test, N = 6 rats (12 paws) per group], demonstrating that hyperalgesic priming had already developed by 48 h. Of note, since the hyperalgesia induced by MCP-1 was still significant 24 h after its administration (A and B, both p < 0.0001, paired Student's t test), the baseline used to evaluate the effect induced by PGE2 at the 30 min time point was already decreased. For that reason, the change in the mechanical threshold induced by PGE2 injection appears smaller (left graphics). The schematic in A shows the hypothetical pathway of a signal triggered by the injection of the priming agent MCP-1 (1, red syringe) in the peripheral terminal of the nociceptor (in the skin), directed to the cell body (red arrow), which induces changes in the peripheral terminal (blue arrow) detected by evaluating the hyperalgesia evoked by the injection of PGE2 (2, blue syringe). In B, the signal that triggers hyperalgesic priming (1, red syringe) is spinal injection of MCP-1, and directed to the cell body (red arrow), from which the message for the neuroplastic change will spread (blue arrow) to the peripheral terminal (in skin) of the nociceptor, detected by the prolongation of the hyperalgesia evoked by injection of PGE2 in the paw (2, blue syringe).
Figure 3.
Figure 3.
Hyperalgesic priming can be detected at the spinal cord when it is induced at the hindpaw. Rats received intradermal injection of the PKCε activator ψεRACK (1 μg, black bars) into the dorsum of the right hindpaw. Vehicle (white bars) was injected into the left paw. Four days later, PGE2 (20 ng/μl, 20 μl) was injected into the spinal cord, and the mechanical nociceptive paw withdrawal thresholds evaluated, 30 min and 4 h after PGE2 injection. Average paw withdrawal thresholds before the injection of ψεRACK or vehicle and immediately before the intrathecal injection of PGE2 (4 d later) were as follows: 119.1 ± 1.2 and 117.5 ± 1.2 g, respectively, for the vehicle group (t(11) = 1.101; p = 0.2945, NS); 119.6 ± 1.8 and 119.5 ± 1.3 g, respectively, for the ψεRACK group (t(11) = 0.1121; p = 0.9127, NS); paired Student's t test showed no significant difference between these two values. We observed a statistically significant increase in the magnitude of the hyperalgesia induced by the injection of PGE2 in the paws previously treated with ψεRACK when compared with the vehicle-treated paws [30 min after PGE2: **p < 0.01; 4 h after PGE2: ***p < 0.001; two-way repeated-measures ANOVA followed by Bonferroni post-test, N = 6 rats (12 paws) per group], showing the presence of hyperalgesic priming (F(1,22) = 35.20, p < 0.0001, when comparing both groups). The schematic on the left shows the signal triggered by the injection of ψεRACK (1, red syringe) at the peripheral terminal of the nociceptor in the skin, directed to the cell body (red arrow), and the signal from the cell body to the central terminal (blue arrow), where the presence of hyperalgesic priming can be detected by evaluating the hyperalgesia evoked by intrathecal injection of PGE2 (2, blue syringe).
Figure 4.
Figure 4.
Hyperalgesic priming at the central terminal of the nociceptor, in the spinal cord, depends on local protein translation. Rats that received spinal intrathecal injection of TNFα (B, 20 ng/μl, 20 μl), IL-6 (C, 1 ng/μl, 20 μl), NGF (D, 150 ng/μl, 20 μl), or MCP-1 (E, 20 ng/μl, 20 μl) 1 week before were tested for hyperalgesic priming of the response to PGE2 (100 ng) injected intradermally into the dorsum of the hindpaw, in the presence or absence of the protein translation inhibitor cordycepin (1 μg, injected at the same site as PGE2 15 min before). Average paw withdrawal thresholds before the intrathecal injections of the priming stimuli and before the injection of PGE2 (1 week later) were as follows: TNFα, 120.6 ± 2.7 and 119.0 ± 2.2 g, respectively, for the vehicle-treated group (t(5) = 0.7734; p = 0.4743, NS) and 118.3 ± 1.4 and 118.3 ± 2.0 g, respectively, for the cordycepin-treated group (t(5) = 0.000; p = 1.000, NS); IL-6, 120.6 ± 1.8 and 120.0 ± 1.2 g, respectively, for the vehicle-treated group (t(5) = 0.3953; p = 0.7089, NS) and 122.6 ± 1.6 and 121.3 ± 2.9 g, respectively, for the cordycepin-treated group (t(5) = 0.0984; p = 0.5160, NS); NGF, 121.6 ± 2.2 and 119.6 ± 1.4 g, respectively, for the vehicle-treated group (t(5) = 1.369; p = 0.2292, NS) and 119.0 ± 1.8 and 118.6 ± 0.8 g, respectively, for the cordycepin-treated group (t(5) = 0.1465; p = 0.8893, NS); MCP-1, 118.6 ± 0.8 and 117.3 ± 1.2 g, respectively, for the vehicle-treated group (t(11) = 0.9834; p = 0.3466, NS) and 120.6 ± 1.0 and 119.6 ± 0.9 g, respectively, for the cordycepin-treated group (t(11) = 0.9199; p = 0.3774, NS); paired Student's t test showed no significant difference between these two values. The nociceptive mechanical paw withdrawal threshold was evaluated 30 min and 4 h after PGE2 injection. Two-way repeated-measures ANOVA followed by Bonferroni post-test showed significant attenuation of PGE2-induced hyperalgesia at the fourth hour after injection in the groups pretreated with cordycepin (***p < 0.001 in all cases, when vehicle- and cordycepin-treated groups are compared at the fourth hour; B, F(1,10) = 126.19; C, F(1,10) = 53.36; D, F(1,10) = 60.63; E, F(1,22) = 63.07; p < 0.0001 for all cases, when vehicle and cordycepin groups are compared), indicating a role of local protein translation in hyperalgesic priming induced by spinal injection of TNFα, IL-6, NGF, or MCP-1 [N = 3 rats (6 paws, B–D) or N = 6 rats (12 paws, E) per group]. A, In the schematic, the red arrow represents the signal triggered by the spinal injection (red syringe) of the priming agents (1, TNFα, IL-6, NGF, and MCP-1) originating in the central terminal of the nociceptor and the subsequent signal (blue arrow) to the peripheral nociceptor terminal (in skin) where hyperalgesic priming is detected by the prolongation of hyperalgesia evoked by PGE2 injected in the paw (2, blue syringe). The green syringe represents the site where cordycepin (or vehicle) was injected.
Figure 5.
Figure 5.
Inhibition of protein translation only reverses priming at the terminal where it is administered. Rats received intradermal injection of the PKCε activator ψεRACK (1 μg) into the dorsum of the hindpaw (lefts panels) or spinal intrathecal injection of MCP-1 (20 ng/μl, 20 μl; right panels). No significant difference between the mechanical thresholds before and 4 d after the injections (when the experiments were performed) was observed (paired Student's t test, data not shown); the average paw withdrawal thresholds before and 4 d after injection of ψεRACK (left panels) were 119.9 ± 0.8 and 119.6 ± 0.7 g, respectively (t(47) = 0.5329; p = 0.5966, NS). For the rats treated with intrathecal injection of MCP-1 (right panels), the average paw withdrawal thresholds before and 4 d after injection were 116.7 ± 0.6 and 116.7 ± 0.7 g, respectively (t(95) = 0.07275; p = 0.9422, NS). Rats were then divided into groups, vehicle (white bars) or the protein translation inhibitor cordycepin (black bars), which were administered intrathecally to the spinal cord (200 ng/μl, 20 μl) or injected into the hindpaw (1 μg). Fifteen minutes later, PGE2 was injected into the dorsum of the hindpaw (100 ng, A) or into the spinal cord (20 ng/μl, 20 μl, B), and the paw withdrawal thresholds were evaluated 30 min and 4 h later. Importantly, cordycepin alone did not affect the mechanical paw withdrawal threshold. However, when it was injected at the same site as PGE2, the PGE2-induced hyperalgesia was significantly attenuated at the 4 h time point (A, left: F(1,10) = 129.42, ***p < 0.001; A, right: F(1,22) = 63.07, ***p < 0.001; B, left: F(1,10) = 28.58, **p = 0.0003; B, right: F(1,22) = 51.52, ***p < 0.001, when the hyperalgesia at 30 min and 4 h are compared, two-way repeated-measures ANOVA followed by Bonferroni post-test). In contrast, when cordycepin was administered at the opposite terminal of the nociceptor from the terminal at which the nociceptive testing was performed, the prolonged PGE2-induced hyperalgesia was not reduced [p > 0.05 in all cases, when comparing vehicle- and cordycepin-treated groups; N = 3 rats (6 paws, ψεRACK treated) or N = 6 rats (12 paws, MCP-1-treated) per group].
Figure 6.
Figure 6.
Systemic treatment with protein translation inhibitor reverses hyperalgesic priming in both the paw and spinal cord. Hyperalgesic priming was induced by intradermal injection of the PKCε activator ψεRACK (1 μg) in the paw (A) or by spinal injection of MCP-1 (20 ng/μl, 20 μl; B). Four days later, as indicated by * in the schematics on the top of the figures, when the mechanical nociceptive paw withdrawal thresholds had returned to baseline values (data not shown), different groups of rats received intravenous vehicles (control groups, white bars), pentostatin (1 mg/kg) plus vehicle (gray bars), or pentostatin plus cordycepin (5 mg/kg, black bars), for 4 consecutive days. On the fifth day, PGE2 (100 ng) was injected into the dorsum of the hindpaw, and the mechanical nociceptive paw withdrawal thresholds were evaluated 30 min and 4 h later. There were no significant differences in the average paw withdrawal thresholds before the injection of PGE2 when compared with the thresholds before the injections of the priming stimuli (paired Student's t test): A: vehicle-plus-vehicle group, 111.6 ± 1.6 and 112.3 ± 1.7 g, respectively (t(5) = 0.2454; p = 0.8159, NS); pentostatin-plus-vehicle group, 108.3 ± 3.0 and 111.6 ± 0.9 g, respectively (t(5) = 1.300; p = 0.2504, NS); cordycepin-plus-pentostatin group, 120.0 ± 2.5 and 118.0 ± 2.0 g, respectively (t(5) = 0.7746; p = 0.4736, NS); B: vehicle-plus-vehicle group, 117.6 ± 2.6 and 114.3 ± 2.0 g, respectively (t(5) = 1.976; p = 0.1051, NS); pentostatin-plus-vehicle group, 111.6 ± 1.6 and 111.0 ± 1.3 g, respectively (t(5) = 0.5976; p = 0.5761, NS); cordycepin-plus-pentostatin group, 113.3 ± 2.1 and 112.0 ± 1.0 g, respectively (t(5) = 0.7906; p = 0.4650, NS). Of note, the systemic treatment with the vehicles, pentostatin, or cordycepin (or the combinations), after priming was induced (4 d after injection of ψεRACK or MCP-1) did not induce significant changes on the mechanical thresholds: A: vehicle-plus-vehicle group, t(5) = 1.118; p = 0.3144, NS; pentostatin-plus-vehicle group, t(5) = 0.4152; p = 0.6452, NS; cordycepin-plus-pentostatin group, t(5) = 0.1395; p = 0.8945, NS; B, vehicle-plus-vehicle group, t(5) = 1.400; p = 0.2204, NS; pentostatin-plus-vehicle group, t(5) = 2.739; p = 0.4090, NS; cordycepin-plus-pentostatin group, t(5) = 0.6523; p = 0.5430, NS. Two-way repeated-measures ANOVA followed by Bonferroni post-test showed that in the groups treated with cordycepin plus pentostatin, but not in the controls (vehicles or pentostatin plus vehicle), the hyperalgesia induced by PGE2 was significantly attenuated at the fourth hour [A: ***p < 0.001, when the PGE2-induced hyperalgesia at the 4 h time point in the cordycepin-plus-pentostatin group is compared with the control groups: cordycepin-plus-pentostatin × vehicles group: F(1,50) = 62.66, p < 0.0001; cordycepin-plus-pentostatin × pentostatin-plus-vehicle groups: F(1,50) = 58.22, p < 0.0001; nonsignificant (F(1,50) = 6.45, p > 0.05) difference was observed between vehicles × pentostatin-plus-vehicle groups; B: ***p < 0.001, when the PGE2-induced hyperalgesia at the 4 h time point in the cordycepin-plus-pentostatin is compared with the control groups: cordycepin-plus-pentostatin × vehicles group: F(1,20) = 16.30, p = 0.0024; cordycepin-plus-pentostatin × pentostatin-plus-vehicle groups: F(1,20) = 22.67, p = 0.0008; nonsignificant difference (F(1,20) = 0.01, p = 0.9394) was observed between vehicles × pentostatin-plus-vehicle groups], showing reversal of the ψεRACK- and MCP-1-induced hyperalgesic priming by systemic treatment with cordycepin. In addition, when tested for priming again by intradermal injection of PGE2 20 d later, the hyperalgesia at the fourth hour was still attenuated in the groups previously treated with cordycepin plus pentostatin (A, ***p < 0.001, when compared with the control groups), showing that the reversal of priming was very long lasting [N = 3 rats (6 paws) per group].
Figure 7.
Figure 7.
Knockdown of CREB prevents (A), but does not reverse (B), hyperalgesic priming. A, Rats were treated with daily spinal intrathecal injections of ODN AS (black bars) for CREB mRNA, for 3 consecutive days, to decrease its levels in the sensory neuron and prevent its activation by the priming inducers ψεRACK (1 μg, injected intradermally into the dorsum of the hindpaws; A, left) or MCP-1 (20 ng/μl; 20 μl, injected by the intrathecal route; A, right), injected on the fourth day. Control animals were treated, following the same protocol, with missense (MS; white bars). To prevent further activation of a signaling pathway that will ultimately produce priming during the acute effect of ψεRACK or MCP-1, the ODN treatments continued until the return of the mechanical nociceptive paw withdrawal thresholds to baseline values, when hyperalgesic priming was assessed by the administration of PGE2 (100 ng). PGE2 was injected intradermally into the dorsum of the hindpaw, and the mechanical threshold was evaluated 30 min and 4 h later. Average paw withdrawal thresholds before the injections of the priming stimuli and before the injection of PGE2 (8 d later) were as follows: ψεRACK in the paw, left, 121.3 ± 1.9 and 121.9 ± 1.4 g, respectively, for the CREB MS-treated group (t(11) = 0.000; p = 1.0000, NS), and 125.9 ± 1.7 and 125.5 ± 1.1 g, respectively, for the AS-treated group (t(11) = 0.1461; p = 0.8864, NS); MCP-1, intrathecally, right, 123.3 ± 2.5 and 120.5 ± 1.7 g, respectively, for the MS-treated group (t(11) = 1.787; p = 0.1014, NS) and 120.6 ± 2.3 and 116.5 ± 1.4 g, respectively, for the AS-treated group (t(11) = 1.948; p = 0.0773, NS). Paired Student's t test showed no significant difference between these two values. Two-way repeated-measures ANOVA followed by Bonferroni post-test showed significant mechanical hyperalgesia induced by PGE2 30 min after the injection. However, while in the MS-treated groups the magnitude of PGE2 hyperalgesia was still significant at the fourth hour, in the AS-treated groups it was strongly attenuated in both the ψεRACK- and the MCP-1-primed group (***p < 0.001 when the MS- and the AS-treated groups are compared). When tested again for priming with PGE2 1 week after the last treatment with ODN AS or MS, a time point when the levels of CREB had returned to pre-AS levels, the prolongation of PGE2-induced hyperalgesia was still attenuated (at the 4 h time point) in the ODN AS-treated groups, but not in the MS-treated groups, indicating a role of CREB in the induction of hyperalgesic priming [***p < 0.001 when the MS- and the AS-treated groups are compared; A, N = 6 rats (12 paws) per group]. Of note, no difference in the mechanical thresholds was observed at this time point, when compared with pre-priming stimuli thresholds: ψεRACK, left, t(11) = 0.8710; p = 0.4024 (NS) for the CREB MS-treated group, and t(11) = 1.497; p = 0.1624 (NS) for the AS-treated group; MCP-1, right, t(11) = 2.482; p = 0.305 (NS) for the MS-treated group, and t(11) = 1.915; p = 0.0819 (NS) for the AS-treated group (paired Student's t test). B, Rats that were treated with intradermal injection of the PKCε activator ψεRACK (1 μg) into the dorsum of the hindpaw (B, left) or spinal intrathecal injection of MCP-1 (20 ng/μl, 20 μl; B, right) 2 weeks before were treated with ODN AS (black bars) for CREB mRNA for 3 consecutive days to decrease the levels of CREB in the nociceptor. Control animals were treated, following the same protocol, with MS (white bars). On the fourth day, PGE2 (100 ng) was injected intradermally into the dorsum of the hindpaws, and the mechanical thresholds were evaluated 30 min and 4 h later. Average paw withdrawal thresholds before the injections of ψεRACK or MCP-1 and before the injection of PGE2 were as follows: ψεRACK, left, 121.6 ± 2.7 and 123.3 ± 1.6 g, respectively, for the CREB MS-treated group (t(11) = 0.8752; p = 0.4002, NS), and 113.3 ± 1.8 and 112.6 ± 2.1 g, respectively, for the AS-treated group (t(11) = 0.4838; p = 0.6380, NS); MCP-1, right, 114.1 ± 1.4 and 114.6 ± 1.2 g, respectively, for the MS-treated group (t(11) = 0.2536; p = 0.8045, NS) and 117.5 ± 1.7 and 117.5 ± 1.4 g, respectively, for the AS-treated group (t(11) = 0.0000; p = 1.0000, NS). Paired Student's t test showed no significant difference between these two values. Two-way repeated-measures ANOVA followed by Bonferroni post-test showed no difference in the magnitude of the PGE2-induced hyperalgesia at 30 min and 4 h in both the ODN AS- and MS-treated groups (rats primed with ψεRACK: F(1,22) = 1.47, p = 0.2378; rats primed with MCP-1: F(1,22) = 1.39, p = 0.2511), indicating that CREB does not play a role in the maintenance of hyperalgesic priming [B: N = 6 rats (12 paws) per group].
Figure 8.
Figure 8.
Schematic of the proposed axonal and nuclear mechanisms underlying hyperalgesic priming. Our experiments support the hypothesis that an inflammatory event that activates PKCε in nonpeptidergic nociceptors (A) triggers gene transcription in the cell body that is dependent on CREB (B, red arrows). The resultant mRNA species will then be transported to the terminals of the nociceptor (C, blue arrows), where translation mechanisms will take place (D) and, as a consequence, produce hyperalgesic priming. This phenomenon will then be maintained, independently of CREB, by local protein translation at the central and peripheral terminals of the nociceptor (E). The time for the development of priming will depend on the transport of the newly formed mRNA to the peripheral or central terminals of the nociceptor. F, The expression of this neuroplasticity, an increased response to pronociceptive inflammatory cytokines, can be verified by the prolongation of the mechanical hyperalgesia induced by the injection of PGE2 (F).
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