Limits...
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.

No MeSH data available.


Related in: MedlinePlus

Effects of CRF on heat hypersensitivity in wild-type mice.(A) Dose-dependency assessed 5 min after CFR injection. *P < 0.05 compared to latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 ng) (one-way ANOVA, Bonferroni test). (B) Time-course of CFR (100 ng) effects. *P < 0.05 compared to latencies before CCI; #P < 0.05, compared to vehicle-treated group (two-way repeated measures ANOVA, Bonferroni test). In all experiments, CRF was applied at the CCI site and the effects were assessed using Hargreaves test, in hind paws ipsilateral to the CCI on days 2 and 14. Detailed statistical evaluation is presented in Supplementary Table 2. Data are expressed as mean ± SEM. N = 6 mice per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5015056&req=5

f3: Effects of CRF on heat hypersensitivity in wild-type mice.(A) Dose-dependency assessed 5 min after CFR injection. *P < 0.05 compared to latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 ng) (one-way ANOVA, Bonferroni test). (B) Time-course of CFR (100 ng) effects. *P < 0.05 compared to latencies before CCI; #P < 0.05, compared to vehicle-treated group (two-way repeated measures ANOVA, Bonferroni test). In all experiments, CRF was applied at the CCI site and the effects were assessed using Hargreaves test, in hind paws ipsilateral to the CCI on days 2 and 14. Detailed statistical evaluation is presented in Supplementary Table 2. Data are expressed as mean ± SEM. N = 6 mice per group.

Mentions: However, when tested in hypersensitivity to heat (using Hargreaves test), which was demonstrated by significantly shortened withdrawal latencies in paws innervated by injured nerves (Fig. 3), the CRF applied at the CCI site in a wide dose range (20–400 ng) and tested up to 60 min following injections, was ineffective in wild-type mice. Although occasionally there were some statistically significant elevations in paw withdrawal latency (on day 14 when tested for dose-dependency, and on day 2 when tested for time-course), these effects are very small and substantially below the latency measured before CCI, and unlikely to be of biological relevance (Fig. 3). Since CRF was ineffective in wild-type mice, there was no rationale to test it in KO mice in heat hypersensitivity.


Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain
Effects of CRF on heat hypersensitivity in wild-type mice.(A) Dose-dependency assessed 5 min after CFR injection. *P < 0.05 compared to latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 ng) (one-way ANOVA, Bonferroni test). (B) Time-course of CFR (100 ng) effects. *P < 0.05 compared to latencies before CCI; #P < 0.05, compared to vehicle-treated group (two-way repeated measures ANOVA, Bonferroni test). In all experiments, CRF was applied at the CCI site and the effects were assessed using Hargreaves test, in hind paws ipsilateral to the CCI on days 2 and 14. Detailed statistical evaluation is presented in Supplementary Table 2. Data are expressed as mean ± SEM. N = 6 mice per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Effects of CRF on heat hypersensitivity in wild-type mice.(A) Dose-dependency assessed 5 min after CFR injection. *P < 0.05 compared to latencies before CCI (indicated by dashed lines) (paired t-test or Wilcoxon test); #P < 0.05 compared to vehicle-treated group (0 ng) (one-way ANOVA, Bonferroni test). (B) Time-course of CFR (100 ng) effects. *P < 0.05 compared to latencies before CCI; #P < 0.05, compared to vehicle-treated group (two-way repeated measures ANOVA, Bonferroni test). In all experiments, CRF was applied at the CCI site and the effects were assessed using Hargreaves test, in hind paws ipsilateral to the CCI on days 2 and 14. Detailed statistical evaluation is presented in Supplementary Table 2. Data are expressed as mean ± SEM. N = 6 mice per group.
Mentions: However, when tested in hypersensitivity to heat (using Hargreaves test), which was demonstrated by significantly shortened withdrawal latencies in paws innervated by injured nerves (Fig. 3), the CRF applied at the CCI site in a wide dose range (20–400 ng) and tested up to 60 min following injections, was ineffective in wild-type mice. Although occasionally there were some statistically significant elevations in paw withdrawal latency (on day 14 when tested for dose-dependency, and on day 2 when tested for time-course), these effects are very small and substantially below the latency measured before CCI, and unlikely to be of biological relevance (Fig. 3). Since CRF was ineffective in wild-type mice, there was no rationale to test it in KO mice in heat hypersensitivity.

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