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Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain

View Article: PubMed Central - PubMed

ABSTRACT

Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.

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Effects of exogenously applied opioid peptides on mechanical and heat hypersensitivity in wild-type mice.(A) Effects of opioid peptides on mechanical hypersensitivity assessed using von Frey filaments. (B) Effects of opioid peptides on heat hypersensitivity measured using Hargreaves test. In all experiments, opioid peptides were applied at the CCI site and the effects were assessed 5 min later, in hind paws ipsilateral to the CCI on days 2 and 14. *P < 0.05 compared to thresholds or latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 μg) (one-way ANOVA, Bonferroni test). Detailed statistical analysis is presented in Supplementary Table 5. Data are expressed as mean ± SEM. N = 7–8 mice per group.
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f6: Effects of exogenously applied opioid peptides on mechanical and heat hypersensitivity in wild-type mice.(A) Effects of opioid peptides on mechanical hypersensitivity assessed using von Frey filaments. (B) Effects of opioid peptides on heat hypersensitivity measured using Hargreaves test. In all experiments, opioid peptides were applied at the CCI site and the effects were assessed 5 min later, in hind paws ipsilateral to the CCI on days 2 and 14. *P < 0.05 compared to thresholds or latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 μg) (one-way ANOVA, Bonferroni test). Detailed statistical analysis is presented in Supplementary Table 5. Data are expressed as mean ± SEM. N = 7–8 mice per group.

Mentions: The results described above suggest that although exogenous agonists, including peptidergic DAMGO and DPDPE are effective, the endogenous opioid peptides do not attenuate neuropathy-induced heat hypersensitivity. Therefore, in the following experiments we assessed whether these effects can be mimicked by exogenously applied opioid peptides and whether they are limited to heat hypersensitivity by also testing them in mechanical hypersensitivity. Indeed, we found that END (0.5–4 μg), ENK (0.5–4 μg) and DYN (0.0625–0.25 μg) applied at the CCI site dose-dependently reversed mechanical hypersensitivity (Fig. 6A), but did not attenuate heat hypersensitivity neither on day 2 nor 14 following CCI (Fig. 6B).


Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain
Effects of exogenously applied opioid peptides on mechanical and heat hypersensitivity in wild-type mice.(A) Effects of opioid peptides on mechanical hypersensitivity assessed using von Frey filaments. (B) Effects of opioid peptides on heat hypersensitivity measured using Hargreaves test. In all experiments, opioid peptides were applied at the CCI site and the effects were assessed 5 min later, in hind paws ipsilateral to the CCI on days 2 and 14. *P < 0.05 compared to thresholds or latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 μg) (one-way ANOVA, Bonferroni test). Detailed statistical analysis is presented in Supplementary Table 5. Data are expressed as mean ± SEM. N = 7–8 mice per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015056&req=5

f6: Effects of exogenously applied opioid peptides on mechanical and heat hypersensitivity in wild-type mice.(A) Effects of opioid peptides on mechanical hypersensitivity assessed using von Frey filaments. (B) Effects of opioid peptides on heat hypersensitivity measured using Hargreaves test. In all experiments, opioid peptides were applied at the CCI site and the effects were assessed 5 min later, in hind paws ipsilateral to the CCI on days 2 and 14. *P < 0.05 compared to thresholds or latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 μg) (one-way ANOVA, Bonferroni test). Detailed statistical analysis is presented in Supplementary Table 5. Data are expressed as mean ± SEM. N = 7–8 mice per group.
Mentions: The results described above suggest that although exogenous agonists, including peptidergic DAMGO and DPDPE are effective, the endogenous opioid peptides do not attenuate neuropathy-induced heat hypersensitivity. Therefore, in the following experiments we assessed whether these effects can be mimicked by exogenously applied opioid peptides and whether they are limited to heat hypersensitivity by also testing them in mechanical hypersensitivity. Indeed, we found that END (0.5–4 μg), ENK (0.5–4 μg) and DYN (0.0625–0.25 μg) applied at the CCI site dose-dependently reversed mechanical hypersensitivity (Fig. 6A), but did not attenuate heat hypersensitivity neither on day 2 nor 14 following CCI (Fig. 6B).

View Article: PubMed Central - PubMed

ABSTRACT

Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides &beta;-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.

No MeSH data available.


Related in: MedlinePlus