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. 2021 Jan 6;41(1):31-46.
doi: 10.1523/JNEUROSCI.2160-20.2020. Epub 2020 Nov 17.

Opioid-Induced Hyperalgesic Priming in Single Nociceptors

Eugen V Khomula  1 , Dionéia Araldi  1 , Ivan J M Bonet  1 , Jon D Levine  2
Affiliations

Opioid-Induced Hyperalgesic Priming in Single Nociceptors

Eugen V Khomula et al. J Neurosci. .

Abstract

Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E2 (PGE2) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and mitogen-activated protein kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel in vitro experiments were performed on small-diameter (<30 µm) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type II priming. Enhancement of the sensitizing effect of a low concentration of PGE2 (10 nm), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4-) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE2 (100 nm) was enhanced. The sensitizing effect of 10 nm PGE2 was attenuated in weakly IB4+ and IB4- neurons cultured from rats whose OIHP was reversed in vivo Thus, in vivo administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4- nociceptors that persists in vitro and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE2 in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.SIGNIFICANCE STATEMENT Commonly used clinical opioid analgesics, such as fentanyl and morphine, can produce hyperalgesia and chronification of pain. To uncover the nociceptor population mediating opioid-induced hyperalgesic priming (OIHP), a model of pain chronification, and elucidate its underlying mechanism, at the cellular level, we established an in vitro model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E2 (PGE2) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE2-induced sensitization was observed in vitro, with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4-)] nociceptors.

Keywords: excitability; fentanyl; isolectin B4; neuroplasticity; nociceptor; sensitization.

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Figures

Figure 1.
Figure 1.
Hyperalgesic priming in the peripheral terminal of the nociceptor, induced by systemic fentanyl, is attenuated by inhibitors of protein translation and a combination of a Src and MAP kinases. A, Male rats received a single systemic injection of an analgesic dose of fentanyl (30 µg/kg, s.c.). Four days later, at which time the mechanical nociceptive threshold was not different from pre-fentanyl baseline (Day 0; t(23) = 1.2; p = 0.26, when the mechanical nociceptive threshold is compared before and 4 d after systemic fentanyl; paired Student's t test), vehicle (2% DMSO in saline, 20 µl), cordycepin (4 µg/20 µl), the combination of Src kinase inhibitor (SU6656, 10 µg/10 µl) and MAPK inhibitor (U0126, 10 µg/10 µl) or the combination of all three inhibitors (cordycepin + SU6656 + U0126: 4 µg/6 µl, 10 µg/6 µl, and 10 µg/6 µl, respectively) was administered intrathecally followed, 10 min later, by PGE2 (100 ng/5 µl) injected intradermally, on the dorsum of the hind paw. Mechanical nociceptive threshold was evaluated 30 min and 4 h after intradermal PGE2. In all groups, PGE2-induced hyperalgesia was measured 30 min after its injection. However, the prolongation of PGE2-induced hyperalgesia at the fourth hour was markedly attenuated in the groups treated with cordycepin, SU6656 + U0126, and the combination of all three inhibitors (F(3,20) = 10.8, ***p = 0.0002, when the vehicle-treated group is compared with the inhibitors-treated groups at the fourth hour after intradermal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). B, Four days after intrathecal treatment with vehicle or inhibitors, at which time the mechanical nociceptive threshold was not different from the pre-vehicle/inhibitor baseline (t(5) = 1.2; p = 0.27, for the vehicle-treated group, t(5) = 0.72; p = 0.51, for the cordycepin-treated group, t(5) = 0.44; p = 0.68, for the combination of Src and MAPK inhibitors-treated group, and t(5) = 1.6; p = 0.17, for the group treated with the combination of all three inhibitors, when the mechanical nociceptive threshold is compared before and after intrathecal inhibitors; paired Student's t test), PGE2 (100 ng/5 µl) was again injected. In the groups previously treated with intrathecal cordycepin, SU6656 + U0126 and the combination of all three inhibitors, prolongation of PGE2-induced hyperalgesia was markedly attenuated (F(3,20) = 23.6, ****p < 0.0001, when the hyperalgesia in the vehicle-treated and the inhibitors-treated groups is compared at the fourth hour after intradermal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). Similarly, 14 d (C) and 28 d (D) after intrathecal injection of vehicle, cordycepin, SU6656 + U0126, or the combination of all three inhibitors, when PGE2 (100 ng/5 µl) was again injected intradermally, the prolongation of PGE2-induced hyperalgesia was still attenuated in all three groups treated with the inhibitors (14 d, C: F(3,20) = 4.1, *p = 0.02; and 28 d, D: F(3,20) = 7.9, **p = 0.0011, when the vehicle-treated group is compared with the inhibitors-treated groups at the fourth hour after intradermal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). These findings support the suggestion that systemic fentanyl induces both Type I and Type II priming, in the peripheral terminal of the nociceptor (n = 6 paws/6 rats per group).
Figure 2.
Figure 2.
Systemic fentanyl induces Type II priming in nociceptor central terminals. A, Male rats were treated with systemic fentanyl (30 µg/kg, s.c.). Four days later, when mechanical nociceptive threshold was not different from pre-fentanyl baseline (t(17) = 0.18, p = 0.86 when the mechanical nociceptive threshold was compared before and 4 d after systemic fentanyl; paired Student's t test), vehicle (2% DMSO in saline, 20 µl), cordycepin (4 µg/10 µl), or the combination of Src inhibitor (SU6656, 10 µg/5 µl) and MAPK inhibitor (U0126, 10 µg/5 µl) were administered intrathecally followed, 10 min later, by PGE2 (400 ng/10 µl) administered at the same site, intrathecally. Mechanical nociceptive threshold was evaluated 30 min and 4 h after intrathecal PGE2. PGE2-induced hyperalgesia was present in all groups, 30 min after its injection. When the prolongation of PGE2-induced hyperalgesia was evaluated at the fourth hour after its injection, in the group treated with the combination of Src and MAPK inhibitors it was markedly attenuated (F(2,15) = 47.9, ****p < 0.0001, when the combination of Src and MAPK inhibitors-treated group is compared with the vehicle-and cordycepin-treated groups at the fourth hour after intrathecal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test); however, no attenuation was observed in the vehicle-treated and cordycepin-treated groups. B, Four days after intrathecal vehicle and inhibitors, when the mechanical nociceptive threshold was not different from pre-vehicle/inhibitor baseline (t(5) = 0.07; p = 0.95, for the vehicle-treated group, t(5) = 0.81; p = 0.46, for the cordycepin-treated group, and t(5) = 0.08; p = 0.94, for the combination of Src and MAPK inhibitors-treated group, when the mechanical nociceptive threshold is compared before and after intrathecal inhibitors; paired Student's t test), PGE2 (400 ng/20 µl) was again injected intrathecally and mechanical nociceptive threshold evaluated 30 min and 4 h later. In the group treated with the combination of Src and MAPK inhibitors the prolongation of PGE2-induced hyperalgesia was still attenuated (F(2,15) = 41.6, ****p < 0.0001, when the combination of Src and MAPK inhibitors-treated group was compared with the vehicle-treated and cordycepin-treated groups, at the fourth hour after intrathecal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). To verify that the reversal of priming in the central terminal of the nociceptor was permanent, intrathecal PGE2 was again injected 14 d (C) and 28 d (D) after intrathecal vehicle or inhibitors. Of note, the cordycepin-treated group was not tested at the next two time points, since it did not show any attenuation in the prolongation of PGE2-induced hyperalgesia in the previous experiments. C, D, In the group of rats treated with the combination of Src and MAPK inhibitors, the prolongation of intrathecal PGE2-induced hyperalgesia was still markedly attenuated at 14 d (C; F(1,10) = 56.4, ****p < 0.0001) and 28 d (D; F(1,10) = 14.3, **p = 0.004, when the vehicle-treated and the combination of Src and MAPK inhibitors-treated groups were compared at the fourth hour after intrathecal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test) after intrathecal vehicle and inhibitors. These findings indicate that at the central terminal of the nociceptor systemic fentanyl induces Type II priming (n = 6 paws/6 rats per group).
Figure 3.
Figure 3.
Role of IB4+ and IB4– nociceptors in priming induced at the peripheral and central nociceptor terminal by systemic fentanyl. Rats received an intrathecal injection of control saporin (3.2 µg/20 µl), SSP-saporin (100 ng/20 µl), or IB4-saporin (3.2 µg/20 µl). Fourteen days later, at which time the mechanical nociceptive threshold was not different from pre-saporin baselines [t(5) = 0.59; p = 0.58, for the saporin (control)-treated group, t(5) = 1.3; p = 0.24, for the SSP-saporin-treated group, and t(5) = 0.47; p = 0.66, for the IB4-saporin-treated group, when the mechanical nociceptive threshold is compared before and 14 d after treatments; paired Student's t test], fentanyl (30 µg/kg) was injected subcutaneously. A, Four days later, at which time mechanical nociceptive threshold was not different from pre-fentanyl baseline [t(5) = 0.25; p = 0.81, for the saporin (control)-treated group, t(5) = 0.52; p = 0.62, for the SSP-saporin-treated group, and t(5) = 0.061; p = 0.95, for the IB4-saporin-treated group, when the mechanical nociceptive threshold was compared before and 4 d after systemic fentanyl; paired Student's t test] PGE2 (100 ng/5 µl) was injected intradermally and mechanical nociceptive threshold evaluated 30 min and 4 h later. Hyperalgesia was present in all saporin-treated groups measured 30 min after its injection. Also, prolonged hyperalgesia induced by intradermal PGE2 was present in all groups treated with saporins (F(2,15) = 0.69, p = 0.52, when all saporin-treated groups are compared at the fourth hour after intradermal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating that in the peripheral terminal of the nociceptor systemic fentanyl does not require IB4+ and SP peptidergic nociceptors to develop priming. B, Seven days after systemic fentanyl and 3 d after intradermal PGE2, rats were tested for priming in the central terminal of the nociceptor. PGE2 (400 ng/20 µl) was injected intrathecally and mechanical nociceptive threshold evaluated 30 min and 4 h later. Intrathecal PGE2-induced hyperalgesia in all saporin-treated groups, measured 30 min after its administration. However, the prolongation of PGE2-induced hyperalgesia at the fourth hour was markedly attenuated in the group treated with SSP-saporin, but not in the saporin-control-treated and IB4-saporin-treated groups [F(2,15) =16.0, ***p = 0.0002, when the SSP-saporin-treated group is compared with the saporin (control)-treated and the IB4-saporin-treated groups at the fourth hour after intrathecal PGE2; two-way repeated-measures ANOVA followed by Bonferroni post hoc test]. These findings support the suggestion that at the central terminal, systemic fentanyl requires IB4– peptidergic nociceptors to induce priming (n = 6 paws/6 rats per group).
Figure 4.
Figure 4.
Illustration of PGE2-induced sensitization in small DRG neurons in vitro. Rows (A–D) represent groups of DRG neurons cultured from rats with different conditions: control (opioid naive, A), fentanyl-primed (B), and fentanyl-primed with reversal of Type I (C) and of Type II (D) priming, as defined in Figures 5–7. Strongly IB4+, weakly IB4+, and IB4– small DRG neurons, sensitized by PGE2, are depicted in each group. For each depicted neuron, its image in transmitted light (DIC contrast; upper left), fluorescent image of IB4-labeling (pseudocolor; upper right), and two electrophysiological recordings (below) are shown. The recordings, made in current clamp mode, show APs (red line) induced by current step of rheobase magnitude, before (lower left) and 10 min after (lower right) administration of PGE2 (10 nm). Stimulation profile is shown as blue line, in the same scale in left and right recordings (the scale differs between neurons). Note, the reduction in rheobase after administration of PGE2, which was used to quantify magnitude of sensitization (further analyzed in Figs. 5–7), is larger in fentanyl-primed group for each IB4-binding status (B) compared with opioid naive group (A); attenuation of the sensitizing effect of PGE2 was observed in both reversal groups (C, D) compared with the primed group (B), in weakly IB4+ and IB4–, but not in strongly IB4+ neurons.
Figure 5.
Figure 5.
Fentanyl-induced priming in vivo is associated with enhanced PGE2-induced sensitization of small DRG neurons, in vitro. Rats were primed by the systemic administration of fentanyl (30 µg/kg, s.c.) 8 d before preparing neuronal cultures, to parallel our in vivo protocol: 4 d before (injection of fentanyl) and 4 d after administering of vehicle or reversal agents. Patch-clamp electrophysiology recordings were made in small-diameter DRG neurons from fentanyl-primed and control (opioid naive) groups (depicted in all panels by the white and dark blue bars, correspondingly), after 24 h in culture. In A–C, bars show pooled magnitudes of decrease in rheobase, relative to preadministration baseline (measured before the first application of PGE2), and 5 min after application (10 and 100 nm); 10 nm PGE2 was applied first, and then, 10 min later, its concentration was increased to 100 nm (cumulative concentration dependence). Symbols show individual values. Only those neurons with a change in rheobase of not <10%, for the higher or lower concentration, were considered for analysis. Some neurons were not tested with the higher concentration because of loss of the patch (but only used if they showed at least 10% reduction in rheobase for the lower concentration), therefore, regular ANOVA was used for analysis. A, Reduction of rheobase in response to 10 and 100 nm PGE2, analyzed regardless of IB4-binding status. In DRG neurons from primed rats the effect of both concentrations of PGE2 was significantly greater than in controls [two-way ANOVA: effect of PGE2 concentration, p = 0.0015, F(1,73) = 10.8; effect of condition: p < 0.0001, F(1,73) = 38.2; not significant (ns) interaction: p = 0.32, F(1,73) = 1.0; Holm–Sidak's post hoc: t(73) = 5.3, ****adjusted p < 0.0001 for 10 nm; t(73) = 3.6, ***adjusted p = 0.0007 for 100 nm]. Number of cells in control group: n = 22 for 10 nm and n = 17 for 100 nm; in primed group: n = 19 for both 10 and 100 nm. B, Reduction of rheobase in response to PGE2 (10 nm), in neurons separated by IB4-binding intensity into: strongly IB4+ (“strong”), weakly IB4+ (“weak”), and IB4– classes (“neg”). Effect of priming was statistically significant (two-way ANOVA: effect of condition F(1,35) = 23.0, p < 0.0001; effect of IB4-binding status F(2,35) = 1.1, p = 0.34; interaction F(2,35) = 1.2, p = 0.33). Holm–Sidak's post hoc test revealed a statistically significant increase in the effect of PGE2 in weakly IB4+ (t(35) = 4.1, ***adjusted p = 0.0008) and IB4– (t(35) = 2.9, *adjusted p = 0.011) classes, indicating a leftward shift in the concentration-response curve for PGE2 in these neurons. In strongly IB4+ neurons, the effect of priming was not statistically significant (t(35) = 1.5, adjusted p = 0.14). Number of cells (strong/weak/neg) in control group: 6/10/6, in primed group: 6/7/6. C, Reduction of rheobase in response to 100 nm PGE2 in strongly IB4+ neurons from the primed group of rats was significantly enhanced compared with the control group (n = 6 per group; two-tailed unpaired Student's t test: t(10) = 3.6, **p = 0.005), indicating a different change in this neuronal population associated with in vivo priming. D, Baseline rheobase (before administration of PGE2) in three neuronal classes with different IB4-binding status. PGE2-sensitive and PGE2-insensitive neurons were included in the analysis of baseline rheobase. Differences between primed and control groups as well as between classes were not statistically significant [two-way ANOVA: effect of IB4-binding status, not significant (ns), p = 0.92, F(2,117) = 0.40; effect of condition: ns, p = 0.68, F(1,117) = 0.17; interaction: ns, p = 0.53, F(2,117) = 0.64]. Number of cells (strong/weak/neg) in control group: 20/23/20, in primed group: 18/24/18.
Figure 6.
Figure 6.
Effect of in vivo treatment of fentanyl-primed rats with the reversal agent for Type I priming on PGE2-induced sensitization of small DRG neurons. Rats were primed by the systemic administration of fentanyl (30 µg/kg, s.c.) 8 d before preparing neuronal cultures (4 d before intrathecal cordycepin, followed by an additional 4 d before culture preparation). Recordings were made in small-diameter DRG neurons from fentanyl-primed animals either treated (reversal group) or not treated (primed group) with cordycepin (depicted in A–C by the blue and dark blue bars, correspondingly) after 24 h in culture. In A–D, bars show pooled magnitudes of decrease in rheobase, relative to baseline, after PGE2 application (10 and 100 nm), measured and analyzed in the same way as described in Figure 5 and Materials and Methods. Symbols show individual values. In A–C, values for primed group were repeated from Figure 5A–C for the purpose of comparison. A, Reduction of rheobase in response to 10 and 100 nm PGE2, analyzed regardless of IB4-binding status. In neurons from primed rats the effect of 10 nm but not 100 nm PGE2 was significantly greater than in the reversal group [two-way ANOVA; effect of condition: F(1,68) = 12.5, p = 0.0007; Holm–Sidak's post hoc: t(68) = 3.2, **adjusted p = 0.004 for 10 nm; t(68) = 1.8, adjusted p = 0.07, not significant (ns), for 100 nm]. Number of cells in primed group: n = 19 for both 10 and 100 nm; in reversal group: n = 19 for 10 nm and n = 15 for 100 nm. B, Reduction of rheobase in response to 10 nm PGE2 in weakly IB4+ (“weak”) and IB4– classes (“neg”) neurons. Attenuation of PGE2-induced sensitization after in vivo cordycepin was statistically significant in both neuronal populations (two-way ANOVA: effect of condition F(1,21) = 16.3, p = 0.0006; Holm–Sidak's post hoc: t(21) = 3.2, **adjusted p = 0.008 for weakly IB4+; t(21) = 2.5, *adjusted p = 0.02 for IB4–). Number of cells (weak/neg) in reversal group: 6/6, in primed group: 7/6. C, Reduction of rheobase in response to 100 nm PGE2 in strongly IB4+ (“strong”) and merged weakly IB4+ and IB4– (“weak and neg”) neurons from primed and reversal groups. Two-way ANOVA revealed statistically significant interaction (F(1,30) = 8.5, p = 0.007), indicating differential effects on the three different neuronal classes. Indeed, statistically significant attenuation in reversal compared with primed group occurred in weakly IB4+ and IB4– but not in strongly IB4+ neurons (Holm–Sidak's post hoc: t(30) = 0.9, adjusted p = 0.38 for strong, not significant (ns); t(30) = 3.7, **adjusted p = 0.002 for weak and neg). Number of cells (strong/weak and neg): 6/13 in primed group, 6/9 in reversal group. D, Reduction of rheobase in response to 100 nm PGE2 in strongly IB4+ (strong), weakly IB4+ (weak), and IB4– (neg) neurons from reversal group. Values in strongly IB4+ class were significantly greater than in weakly IB4+ and IB4– neurons [one-way ANOVA: F(2,12) = 11.8, ** p = 0.002; Tukey's post hoc: q(12) = 6.3, adjusted p = 0.002 for strongly IB4+ vs weakly IB4+; q(12) = 5.2, ##adjusted p = 0.008 for strongly IB4+ vs IB4–; q(12) = 1.3, adjusted p = 0.63, not significant (ns), for weakly IB4+ vs IB4–]. Number of cells: 6 strong, 4 weak, 5 neg.
Figure 7.
Figure 7.
Effect of in vivo treatment of fentanyl-primed rats with reversal agents for Type II priming on PGE2-induced sensitization of small DRG neurons. Rats were primed by the systemic administration of fentanyl (30 µg/kg, s.c.) 8 d before preparing neuronal cultures (4 d before reversal agents, followed by 4 d before culture preparation). Recordings were made in small-diameter DRG neurons from fentanyl-primed animals treated intrathecally with the combination of a Src and MAPK inhibitor (SU6656 + U0126; Type II reversal group; light blue bars) and not treated (primed group; dark blue bars). In A–D, bars show pooled magnitudes of decrease in rheobase after PGE2 application (10 and/or 100 nm), relative to baseline (measured before the first application), measured and analyzed in the same way as described in Figure 6, while symbols show individual values. In A–C, values for primed group were repeated from Figure 5A–C for the purpose of comparison. A, Reduction of rheobase in response to 10 and 100 nm PGE2, analyzed regardless of IB4-binding status. In the primed group the effect of 10 and 100 nm PGE2 was significantly greater than in the Type II reversal group (two-way ANOVA; effect of condition: F(1,70) = 16.6, p = 0.0001; Holm–Sidak's post hoc: t(70) = 3.3, **adjusted p = 0.003 for 10 nm; t(70) = 2.5, *adjusted p = 0.02 for 100 nm). Number of cells in primed group: n = 19 for both 10 and 100 nm; in Type II reversal group: n = 18 for both 10 and 100 nm. B, Reduction of rheobase in response to 10 nm PGE2 in weakly IB4+ (“weak”) and IB4– classes (“neg”) neurons. Attenuation of PGE2-induced sensitization after in vivo administration of the combination of a Src and MAPK inhibitor was statistically significant in both neuronal subpopulations (two-way ANOVA: effect of condition F(1,21) = 15.5, p = 0.0008; Holm–Sidak's post hoc: t(21) = 3.4, **adjusted p = 0.005 for weakly IB4+; t(21) = 2.2, *adjusted p = 0.04 for IB4–). Number of cells (weak/neg) in Type II reversal group: 6/6, in primed group: 7/6. C, Reduction of rheobase in response to 100 nm PGE2 in strongly IB4+ (“strong”) and merged weakly IB4+ and IB4– (“weak and neg”) neurons from primed and reversal groups. Two-way ANOVA revealed statistically significant interaction (F(1,33) = 8.8, p = 0.006), indicating differential effects on different neuronal classes. Indeed, statistically significant attenuation in reversal group compared with the primed group occurred in weakly IB4+ and IB4– but not in strongly IB4+ neurons [Holm–Sidak's post hoc: t(33) = 0.74, adjusted p = 0.46 for strong, not significant (ns); t(33) = 4.1, ***adjusted p = 0.0005 for weak and neg]. Number of cells (strong/weak and neg): 6/13 in primed group, 6/12 in Type II reversal group. D, Reduction of rheobase in response to 100 nm PGE2 in strongly IB4+ (strong), weakly IB4+ (weak), and IB4– (neg) neurons from reversal group. Reduction of rheobase in the strongly IB4+ class were significantly greater than in weakly IB4+ and IB4– neurons [one-way ANOVA: F(2,15) = 11.2, p = 0.0010; Tukey's post hoc: q(15) = 4.8, *adjusted p = 0.011 for strongly IB4+ vs weakly IB4+; q(15) = 6.5, **adjusted p = 0.0010 for strongly IB4+ vs IB4–; q(15) = 1.7, adjusted p = 0.48, not significant (ns), for weakly IB4+ vs IB4–]. Number of cells: 6 strong, 6 weak, 6 neg.
Figure 8.
Figure 8.
Priming by fentanyl in vivo as well as in vivo reversal of priming does not alter baseline rheobase of small DRG neurons in vitro. Bars show pooled baseline rheobase (before administration of PGE2) in the whole neuronal population (regardless of IB4-binding status) in control, primed, and two reversal groups, as defined in Figures 5–7. Symbols show individual values. PGE2-sensitive and PGE2-insensitive neurons were included in the analysis. Difference between groups was not statistically significant (one-way ANOVA: p = 0.26, F(3,196) = 1.33). Number of cells: 63 in control, 61 in primed, 41 in Type I, and 35 in Type II reversal groups.
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