Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat - PubMed (original) (raw)

Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat

Christopher M Peters et al. Anesthesiology. 2015 Apr.

Abstract

Background: Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models.

Methods: CPM was assessed in individual rats and correlated with each animal's time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine β-hydroxylase-conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation.

Results: The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine β-hydroxylase-saporin. Dopamine β-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine β-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery.

Conclusion: Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

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Figures

Figure 1

Figure 1

Endogenous analgesia was measured in rats by assessing conditioned pain modulation (CPM). A, Hindpaw withdrawal paw pressure thresholds (test stimuli) were assessed in rats after injection of capsaicin (150 μg/ 50 μl) or vehicle solution into the forepaw (conditioning stimuli). Rats received spinal injections of the α2 adrenergic receptor antagonist idazoxan (30μg, i.t.) or saline solution via lumbar puncture 10 minutes prior to forepaw capsaicin to examine the contribution of noradrenergic mechanisms in this model of CPM. Two-way ANOVA with Bonferroni multiple comparisons. Values represent mean ± SD with n=6 per group. # p < 0.025 vs. pre-capsaicin baseline. * p < 0.0125 vs. capsaicin + saline group. B, Spinal ablation of noradrenergic fibers with DβH-saporin (5 μg, i.t.) 14 days prior to testing also partially reduced CPM. Student’s t-test, * p < 0.05. Values represent mean ± SD with n=8 for the IgG-saporin group and n=8 for the DβH-saporin treated group. C, Time course of spinal norepinephrine release in the lumbar region of the spinal cord following injection of capsaicin into the forepaw. Two-way ANOVA with Bonferroni multiple comparisons. Values represent mean ± SD with n=6 for the capsaicin group and n=4 for the vehicle treated group. cap = capsaicin; DβH = dopamine β hydroxylase; IgG = immunoglobulin G; i.t. = intrathecal; NE = norepinephrine

Figure 2

Figure 2

Time course of mechanical hypersensitivity and static weight bearing following partial L5 spinal nerve ligation (pSNL). Rats received intrathecal treatment with DβH-saporin or control IgG saporin 14 days prior to surgery and were assessed for mechanical hypersensitivity with von Frey filaments and assayed for shifts in weight bearing on the ipsilateral hindpaw. Mechanical withdrawal thresholds were reduced in the ipsilateral (A) and contralateral (B) paw of DβH-saporin treated rats. Two-way RM ANOVA with Bonferroni multiple comparisons. * p < 0.003 for within time point comparison to pSNL + IgG saporin values or # p < 0.003 for within treatment group comparisons to Pre-surgery baseline value. Brackets indicate the data points which withdrawal thresholds were significantly different from Pre-surgery values. The percentage body weight shifted to the ipsilateral paw was reduced in pSNL rats from both groups for approximately 2 weeks (C). A significantly greater shift in weight bearing was present in DβH-saporin compared to IgG saporin treated rats particularly at early time points. Two-way RM ANOVA with Bonferroni multiple comparisons. * p < 0.003 for within time point comparison to pSNL + IgG saporin values or # p < 0.003.Values represent mean± SEM with n=7 for DβH-saporin and n=8 for IgG saporin group. DβH = dopamine β hydroxylase; IgG = immunoglobulin G; i.t. = intrathecal; RM = repeated measures

Figure 3

Figure 3

Modeled trajectories of recovery from mechanical hypersensitivity after pSNL in rats treated with DβH-saporin or control IgG saporin 14 days prior to surgery. Longitudinal behavioral measurements of mechanical paw withdrawal thresholds from the ipsilateral paw of individual rats modeled using growth curve analysis were best fit to a linear function described by an intercept (modeled withdrawal threshold immediately following pSNL surgery) and slope (linear rate of change in withdrawal threshold after pSNL surgery) (A). Group trajectories depict the mean fit for all the animals within each treatment group with 95% confidence intervals indicated by shading (B). DβH = dopamine β hydroxylase; IgG = immunoglobulin G; pSNL = partial spinal nerve ligation

Figure 4

Figure 4

Representative images of noradrenergic innervation and glial activation in ipsilateral dorsal spinal cord 70 days following partial spinal nerve ligation (pSNL) in rats treated with spinal DβH-saporin (A, C, E) or IgG-saporin (B, D, E) 14 days prior to surgery. A, B: Long term depletion of spinal noradrenergic fibers is evident in the dorsal spinal cord of DβH-saporin treated rats based on loss of DβH-immunoreactivity (IR). IBA1-IR (C, D) and GFAP-IR (E,F) were increased in the superficial dorsal horn of nerve injured rats with depletion of noradrenergic fibers. Lower panels depict quantification of spinal cord IBA1 (G) and GFAP-IR (H) levels. Values represent median ± 25th and 75th percentile with n= 7 for DβH-saporin and n=8 for IgG-saporin group. Data were analyzed with Mann Whitney rank sum test. * P< 0.05 within side comparison to pSNL + IgG-saporin value. Scale bar in F = 200 μm. DβH = dopamine β hydroxylase; IgG = immunoglobulin G; contra = contralateral; ipsi = ipsilateral, IBA1 = ionized calcium binding adapter molecule 1; GFAP = glial fibrillary acidic protein; IR = immunoreactivity

Figure 5

Figure 5

Spinal norepinephrine tonically inhibits mechanical hypersensitivity after partial spinal nerve ligation (pSNL). Rats received intrathecal treatment with DβH-saporin or IgG-saporin 91 days after pSNL surgery (approximately 7 weeks after mechanical hypersensitivity resolved). Mechanical hypersensitivity was reinstated in the ipsilateral (A) and contralateral (B) paw of DβH-saporin treated rats. Two-way repeated measures ANOVA with Bonferroni multiple comparisons. * p < 0.002 for within timepoint comparison to pSNL + IgG saporin values or # p < 0.003 for within treatment group comparisons to Pre-surgery baseline value. Values represent mean ± SD with n=6 per group. In the same groups of rats, norepinephrine content was significantly reduced in the dorsal spinal cord of DβH-saporin treated pSNL rats compared to IgG saporin treated pSNL rats (C). Norepinephrine content examined in a separate group of normal and pSNL rats showed increased content three weeks postoperatively that persisted through fifteen weeks. Kruskal-Wallis one-way analysis of variance on ranks using pairwise multiple comparison procedures (Student –Newman-Keuls method) or Mann Whitney Rank Sum test * p< 0.05 vs. normal. % p < 0.05 vs. pSNL (D106) +IgG-saporin. # p< 0.05 vs. contra within group comparison. Values represent median ± 25th and 75th percentile with n=6 per group. DβH = dopamine β hydroxylase; IgG = immunoglobulin G; contra = contralateral; ipsi = ipsilateral; i.t. = intrathecal; NE = norepinephrine

Figure 6

Figure 6

Preoperative conditioned pain modulation (CPM) correlated with timecourse of postoperative resolution of mechanical hypersensitivity after partial L5 spinal nerve ligation (pSNL). A, Twenty four hours prior to pSNL surgery CPM was tested in 19 individual rats. Rats produced a variable increase in hindpaw pressure thresholds 30 minutes following intraplantar administration of capsaicin (150 μg/ 50 μl) into the forepaw. Values for individual rats are displayed as a gradient with lower CPM in blue and greater CPM in red. B, Paw withdrawal thresholds to mechanical stimulation were assessed for ten weeks following pSNL surgery and individual daily withdrawal thresholds were recorded. C, Individual repeated daily withdrawal thresholds were analyzed using growth curve analysis to better model the change in mechanical withdrawal thresholds over time. D, The slope of trajectory of withdrawal thresholds correlated to the preoperative difference in CPM as rats with lower endogenous analgesia or CPM had slower resolution of mechanical hypersensitivity. Error bars in D indicate variability in predicted slope over time within individual rats. PPT = paw pressure threshold

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