Systemic Morphine Produces Dose-dependent Nociceptor-mediated Biphasic Changes in Nociceptive Threshold and Neuroplasticity

doi:10.1016/j.neuroscience.2018.11.051

. 2019 Feb 1:398:64-75.

doi: 10.1016/j.neuroscience.2018.11.051. Epub 2018 Dec 7.

Systemic Morphine Produces Dose-dependent Nociceptor-mediated Biphasic Changes in Nociceptive Threshold and Neuroplasticity

Luiz F Ferrari¹, Dioneia Araldi², Oliver Bogen³, Paul G Green⁴, Jon D Levine⁵

Affiliations

¹ Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
² Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
³ Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
⁴ Departments of Preventative & Restorative Dental Sciences and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
⁵ Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].

PMID: 30529265
PMCID: PMC9948647
DOI: 10.1016/j.neuroscience.2018.11.051

Systemic Morphine Produces Dose-dependent Nociceptor-mediated Biphasic Changes in Nociceptive Threshold and Neuroplasticity

Luiz F Ferrari et al. Neuroscience. 2019.

. 2019 Feb 1:398:64-75.

doi: 10.1016/j.neuroscience.2018.11.051. Epub 2018 Dec 7.

Authors

Luiz F Ferrari¹, Dioneia Araldi², Oliver Bogen³, Paul G Green⁴, Jon D Levine⁵

Affiliations

¹ Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
² Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
³ Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
⁴ Departments of Preventative & Restorative Dental Sciences and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].
⁵ Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: [email protected].

PMID: 30529265
PMCID: PMC9948647
DOI: 10.1016/j.neuroscience.2018.11.051

Abstract

We investigated the dose dependence of the role of nociceptors in opioid-induced side-effects, hyperalgesia and pain chronification, in the rat. Systemic morphine produced a dose-dependent biphasic change in mechanical nociceptive threshold. At lower doses (0.003-0.03 mg/kg, s.c.) morphine induced mechanical hyperalgesia, while higher doses (1-10 mg/kg, s.c.) induced analgesia. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to mu-opioid receptor (MOR) mRNA, attenuated both hyperalgesia and analgesia. 5 days after systemic morphine (0.03-10 mg/kg s.c.), mechanical hyperalgesia produced by intradermal (i.d.) prostaglandin E₂ (PGE₂) was prolonged, indicating hyperalgesic priming at the peripheral terminal of the nociceptor. The hyperalgesia induced by i.t. PGE₂ (400 ng/10 µl), in groups that received 0.03 (that induced hyperalgesia) or 3 mg/kg (that induced analgesia) morphine, was also prolonged, indicating priming at the central terminal of the nociceptor. The prolongation of the hyperalgesia induced by i.d. or i.t. PGE₂, in rats previously treated with either a hyperalgesic (0.03 mg/kg, s.c.) or analgesic (3 mg/kg, s.c.) dose, was reversed by i.d. or i.t. injection of the protein translation inhibitor cordycepin (1 µg), indicative of Type I priming at both terminals. Although pretreatment with MOR antisense had no effect on priming induced by 0.03 mg/kg morphine, it completely prevented priming by 3 mg/kg morphine, in both terminals. Thus, the induction of hyperalgesia, but not priming, by low-dose morphine, is MOR-dependent. In contrast, induction of both hyperalgesia and priming by high-dose morphine is MOR-dependent. The receptor at which low-dose morphine acts to produce priming remains to be established.

Keywords: hyperalgesic priming; morphine; mu-opioid receptor (MOR); nociceptor; opioid-induced hyperalgesia.

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Conflict of interest statement

Conflict of interest: The authors declare no competing financial interests.

Figures

**Fig. 1.**
Dose–response relationship for the effect of systemic morphine on nociceptive threshold. Male rats (280–320 g) received a subcutaneous injection of vehicle or one dose of morphine (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3 or 10 mg/kg). Mechanical nociceptive threshold was evaluated on the dorsum of the hind paw before and 30 min after injection. While no significant change in mechanical nociceptive threshold was observed in the groups treated with vehicle, comparing mechanical threshold before and after morphine injection using 2-way repeated measures ANOVA there was a significant interaction effect pre- vs. post-morphine at all values of morphine dose (F_9,50 = 30.40, p < 0.0001), with morphine dose (F_9,50 = 15.86, p < 0.0001) and treatment (F_1,50 = 4.28, p < 0.05) significantly affecting the result. Bonferroni’s multiple comparison test showing significant *hyperalgesia* at 0.003 mg/kg (*p = 0.04), 0.01 mg/kg (^**p = 0.027) and 0.03 mg/kg (^***p = 0.006), and significant *analgesia* at 1 mg/kg (^#p = 0.018), 3 mg/kg (^##p < 0.0001) and 10 mg/kg (^##p < 0.0001), indicating a dose-dependent biphasic effect of systemic morphine on the mechanical nociceptive threshold in the rat hind paw. (n = 6 per group).

**Fig. 2.**
Nociceptor MOR-dependent effects of systemic morphine on mechanical nociceptive threshold. Male rats (350–400 g) were treated for 6 consecutive days with i.t. injections of ODN antisense or mismatch against MOR mRNA (120 μg/day); ODN treatment did not affect the mechanical nociceptive threshold (data not shown). On the 4th day of ODN treatment, the mismatch and antisense groups were each divided into two subgroups that received subcutaneous injection of 0.03 or 3 mg/kg of morphine.; mechanical nociceptive thresholds were evaluated before and 30 min after injection. A. *0.03 mg/kg:* When compared to the mismatch groups, the magnitude of the hyperalgesia induced by 0.03 mg/kg of morphine in the antisense group was reduced 51% (t₁₀ = 2.009, *p = 0.0361, unpaired Student’s t-test); B. *3 mg/kg:* When compared to the mismatch groups, the magnitude of the analgesia produced by 3 mg/kg was decreased 36% (t₁₀ = 2.514, ^#p = 0.0307), indicating that the effects of systemic morphine, at both low (hyperalgesic) and high (analgesic) doses on the mechanical threshold are MOR-dependent. (n = 6 per group). C. Western blot analysis of DRG extracts from rats injected with MOR antisense ODN (120 μg/day for three consecutive days) shows a significant decrease in MOR immunoreactivity when compared to extracts from ODN mismatch-treated rats (−23.4 ± 8.4% unpaired Student’s t-test, t10 = 2.737, p = 0.011, n = 6,). Note that the MOR exist in several isoforms with calculated molecular weights between 43.5 and 52 kDa (UniProtKB database entry P33535). GAPDH, which was used as loading control has a calculated molecular weight of ~36 kDa (UniProtKB database entry P04797).

**Fig. 3.**
Systemic morphine induces hyperalgesic priming in nociceptor central and peripheral terminals. Panel A: Groups of rats pretreated with systemic vehicle or different doses of morphine (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3 or 10 mg/kg, Fig. 1) received an i.d. injection of PGE₂ (100 ng) on the dorsum of the hind paw 5 d later, at the site of nociceptive testing. At that time, mechanical nociceptive thresholds were not significantly different from pre-morphine baseline. 2-way repeated measures ANOVA revealed that there is a significant interaction effect of time at all values of morphine dose (F_9,50 = 26.47, p < 0.0001), and significant differences of morphine dose (F_9,50 = 12.89, p < 0.0001), and of time (F_1,50 = 153.25, p < 0.0001). Bonferroni’s multiple comparison test revealed that in the groups that had received morphine 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg, PGE₂-induced hyperalgesia was still present 4 h after injection (i.e. not significantly different from 30 min); in contrast, groups previously treated with vehicle or 0.001, 0.003, and 0.01 mg/kg morphine 5 d before, PGE₂ hyperalgesia was significantly less at 4 h than at 30 min (^****p < 0.0001 for each of these 3 morphine doses and vehicle). Panel B: Rats that had been pretreated with vehicle, or 0.03 or 3 mg/kg of morphine (s.c.), received an i.t.injection of PGE₂ (400 ng/10 μl). 2-way repeated measures ANOVA revealed a significant interaction of time at all values of morphine dose (F_2,15 = 9.18, p = 0.0025), and a significant effect of the dose of morphine (F_2,15 = 14.02, p = 0.0004), but time does not affect the result (F_1,15 = 1.53, p = 0.235). Bonferroni’s multiple comparison test revealed that in vehicle group the magnitude of the hyperalgesia induced by PGE₂ had decreased significantly by the 4th h (^**p = 0.0026), but in the morphine-treated groups, at both doses, it was still present at that time point, without attenuation (0.03 mg/kg p < 0.99; 3 mg/kg p = 0.373). Together, these results show that both low and high doses of systemic morphine induce hyperalgesic priming in both terminals of the nociceptor. (n = 6 per group).

**Fig. 4.**
Systemic morphine induces Type I hyperalgesic priming at the nociceptor peripheral terminal. Upper panels: Groups of rats (350–390 g) were treated with systemic (s.c.) injection of 0.03 or 3 mg/kg of morphine, both of which induce hyperalgesic priming. Five days later, the groups were each divided into 3 subgroups that received i.d. injection of vehicle (control), the protein translation inhibitor cordycepin (1 μg), or a combination of the Src inhibitor SU6656 and the MEK/Erk inhibitor U0126 (both 1 μg), on the dorsum of the hind paw, at the site of nociceptive testing. After 5 min, PGE₂ (100 ng), was injected at the same site. Evaluation of the mechanical nociceptive threshold, before and 5 days after morphine (immediately before the experiment), showed no difference between mechanical nociceptive threshold, pre- and post-morphine (data not shown). In all groups, mechanical hyperalgesia was robust 30 min after PGE₂ injection. 2-way repeated measures ANOVA revealed a significant interaction of time at all values of treatment (*0.03 mg/kg: F*_2,15 = 28.02, p < 0.0001; *3 mg/kg: F*_2,15 = 29.88, p < 0.0001), a significant effect of treatment (*0.03 mg/kg: F*_2,15 = 22.96, p < 0.0001; *3 mg/kg: F*_2,15 = 9.82, p = 0.0019) and time (*0.03 mg/kg: F*_1,15 = 33.70, p < 0.0001; *3 mg/kg: F*_1,15 = 23.51, p = 0.0002). Bonferroni’s multiple comparison shows that for both doses of morphine there was no attenuation in the control and the SU6656+U0126 groups, but a significantly lower PGE₂-induced hyperalgesia in the cordycepin-treated group (both morphine doses ^****p < 0.0001). Lower panels: When PGE₂ was injected again, at the same site, one week later, 2-way repeated measures ANOVA revealed a significant interaction of time at all values of treatment (*0.03 mg/kg: F*_1,10 = 146.19, p < 0.0001; *3 mg/kg: F*_1,10 = 48.83, p < 0.0001), a significant effect of treatment (*0.03 mg/kg: F*_1,10 = 34.75, p = 0.0002; *3 mg/kg: F*_1,10 = 20.90, p = 0.001) and time (*0.03 mg/kg: F*_1,10 = 106.88, p < 0.0001; *3 mg/kg: F*_1,10 = 50.55, p < 0.0001). Bonferroni’s multiple comparison shows that for both doses of morphine there was no attenuation in the control, but a significantly lower PGE₂-induced hyperalgesia at the 4th h in the cordycepin-treated group (^****p < 0.0001).

**Fig. 5.**
Systemic morphine induces Type I hyperalgesic priming at the central terminal of the nociceptor. Upper panels: Groups of rats (360–410 g) were treated systemically (s.c.) with morphine, 0.03 or 3 mg/kg, which induces priming at the central terminal of the nociceptor (Fig. 3B). Five days later, the groups were each divided into 3 subgroups that received i.t. injection of vehicle (control), the protein translation inhibitor cordycepin (4 μg/10 μl), or a combination of the Src inhibitor SU6656 and the MEK/Erk inhibitor U0126 (both 10 μg/5 μl). Five min later, PGE₂ (400 ng/10 μl), was injected, also i.t.. Mechanical nociceptive threshold was measured before and 5 d after the administration of morphine (immediately before the experiment), and 30 min and 4 h after PGE₂ injection. No difference between pre- and post-morphine mechanical thresholds was observed (data not shown). In all groups, robust mechanical hyperalgesia was observed 30 min after i.t. PGE₂. 2-way repeated measures ANOVA revealed significant interaction of time with treatment (*0.03 mg/kg: F*_2,15 = 13.67, p < 0.0004; *3 mg/kg: F*_2,15 = 25.63, p = 0.0001) and a significant effect of treatment for *3 mg/kg* (F_2,15 = 5.78, p = 0.0137) but not for *0.03 mg/kg* (F_2,15 = 3.26, p = 0.0668), and a significant effect of time (*0.03 mg/kg: F*_1,15 = 18.12, p = 0.0007; *3 mg/kg*: F_1,15 = 15.47, p = 0.0013). Bonferroni’s multiple comparison shows that for both morphine 0.03 and 3 mg/kg-treated groups there was no attenuation in the control and the SU6656+U0126 groups, but a significantly lower PGE₂-induced hyperalgesia in the cordycepin-treated group (^****p < 0.0001). Lower panels: When PGE₂ was injected again, at the same site, one week later, 2-way repeated measures ANOVA revealed a significant interaction of time at all values of treatment (*0.03 mg/kg: F*_1,10 = 18.29, p < 0.0016; *3 mg/kg: F*_1,10 = 33.98, p = 0.0002), a significant effect of treatment (*0.03 mg/kg: F*_1,10 = 33.68, p = 0.0002; *3 mg/kg: F*_1,10 = 28.39, p = 0.0003) and time (*0.03 mg/kg: F*_1,10 = 18.52, p < 0.0016; *3 mg/kg: F*_1,10 = 23.65, p < 0.0007). Bonferroni’s multiple comparison shows that for both doses of morphine there was no attenuation in the control, but a significantly lower PGE₂-induced hyperalgesia at the 4th h in the cordycepin-treated group (^****p < 0.0001).

**Fig. 6.**
Role of nociceptor MOR in the induction of priming by systemic morphine. Male rats (370–410 g) were treated for 6 consecutive days with i.t. injections of ODN antisense or mismatch against MOR mRNA (120 μg/day). Mechanical nociceptive threshold was not significantly different pre- and post-ODN treatment (data not shown). In all groups, robust mechanical hyperalgesia was observed 30 min after i.t. PGE₂. Upper panels *(Peripheral terminal):*For 0.03 mg/kg morphine, 2-way repeated measures ANOVA revealed no significant interaction of time with treatment (F_1,10 = 0.63, p = 0.4452), treatment (F_1,10 = 1.88, p = 0.1998), or time (F_1,10 = 1.17, p = 0.3054). However, for 3 mg/kg morphine, 2-way repeated measures ANOVA revealed significant interaction of time with treatment (F_1,10 = 22.70, p = 0.0008), treatment (F_1,10 = 19.28, p = 0.0014), or time (F_1,10 = 22.84, p = 0.0007). One week later in the 3 mg/kg-treated group, 2-way repeated measures ANOVA revealed significant interaction of time with treatment (F_1,10 = 44.73, p < 0.0001), treatment (F_1,10 = 36.69, p = 0.0001), or time (F_1,10 = 58.74, p < 0.0001). Lower panels *(Central terminal):* For 0.03 mg/kg morphine, 2-way repeated measures ANOVA revealed no significant interaction of time with treatment (F_1,10 = 0.56, p = 0.4703), treatment (F_1,10 = 1.86, p = 0.2021), or time (F_1,10 = 0.20, p = 0.6607). However, for 3 mg/kg morphine, 2-way repeated measures ANOVA revealed significant interaction of time with treatment (F_1,10 = 26.47, p = 0.0004), treatment (F_1,10 = 18.39, p = 0.0016), or time (F_1,10 = 42.48, p < 0.0001). One week later in the 3 mg/kg-treated group, 2-way repeated measures ANOVA revealed significant interaction of time with treatment (F_1,10 = 33.85, p = 0.0002), treatment (F_1,10 = 44.18, p < 0.0001), or time (F_1,10 = 12.76, p = 0.0051).

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References

1. Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD Hypotonicity induces TRPV4-mediated nociception in rat Neuron, 39 (2003), pp. 497–511, 10.1016/S0896-6273(03)00462-8 - DOI - PubMed
1. Aley KO, Messing RO, Mochly-Rosen D, Levine JD Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C J Neurosci, 20 (2000), pp. 4680–4685, 10.1523/JNEUROSCI.20-12-04680.2000 - DOI - PMC - PubMed
1. Andersson HI, Ejlertsson G, Leden I, Rosenberg C Chronic pain in a geographically defined general population: studies of differences in age, gender, social class, and pain localization Clin J Pain, 9 (1993), pp. 174–182, 10.1097/00002508-199309000-00004 - DOI - PubMed
1. Araldi D, Ferrari LF, Levine JD Repeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain J Neurosci, 35 (2015), pp. 12502–12517, 10.1523/JNEUROSCI.1673-15.2015 - DOI - PMC - PubMed
1. Araldi D, Ferrari LF, Levine JD Gi-Protein Coupled 5-HT1B/D Receptor Agonist Sumatriptan Induces Type I Hyperalgesic Priming Pain (2016), 10.1097/j.pain.0000000000000581 - DOI - PMC - PubMed

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[1] Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD Hypotonicity induces TRPV4-mediated nociception in rat Neuron, 39 (2003), pp. 497–511, 10.1016/S0896-6273(03)00462-8 - DOI - PubMed

[2] Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD Hypotonicity induces TRPV4-mediated nociception in rat Neuron, 39 (2003), pp. 497–511, 10.1016/S0896-6273(03)00462-8 - DOI - PubMed

[3] Aley KO, Messing RO, Mochly-Rosen D, Levine JD Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C J Neurosci, 20 (2000), pp. 4680–4685, 10.1523/JNEUROSCI.20-12-04680.2000 - DOI - PMC - PubMed

[4] Aley KO, Messing RO, Mochly-Rosen D, Levine JD Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C J Neurosci, 20 (2000), pp. 4680–4685, 10.1523/JNEUROSCI.20-12-04680.2000 - DOI - PMC - PubMed

[5] Andersson HI, Ejlertsson G, Leden I, Rosenberg C Chronic pain in a geographically defined general population: studies of differences in age, gender, social class, and pain localization Clin J Pain, 9 (1993), pp. 174–182, 10.1097/00002508-199309000-00004 - DOI - PubMed

[6] Andersson HI, Ejlertsson G, Leden I, Rosenberg C Chronic pain in a geographically defined general population: studies of differences in age, gender, social class, and pain localization Clin J Pain, 9 (1993), pp. 174–182, 10.1097/00002508-199309000-00004 - DOI - PubMed

[7] Araldi D, Ferrari LF, Levine JD Repeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain J Neurosci, 35 (2015), pp. 12502–12517, 10.1523/JNEUROSCI.1673-15.2015 - DOI - PMC - PubMed

[8] Araldi D, Ferrari LF, Levine JD Repeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain J Neurosci, 35 (2015), pp. 12502–12517, 10.1523/JNEUROSCI.1673-15.2015 - DOI - PMC - PubMed

[9] Araldi D, Ferrari LF, Levine JD Gi-Protein Coupled 5-HT1B/D Receptor Agonist Sumatriptan Induces Type I Hyperalgesic Priming Pain (2016), 10.1097/j.pain.0000000000000581 - DOI - PMC - PubMed

[10] Araldi D, Ferrari LF, Levine JD Gi-Protein Coupled 5-HT1B/D Receptor Agonist Sumatriptan Induces Type I Hyperalgesic Priming Pain (2016), 10.1097/j.pain.0000000000000581 - DOI - PMC - PubMed

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Systemic Morphine Produces Dose-dependent Nociceptor-mediated Biphasic Changes in Nociceptive Threshold and Neuroplasticity

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Systemic Morphine Produces Dose-dependent Nociceptor-mediated Biphasic Changes in Nociceptive Threshold and Neuroplasticity

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