Skip to main content
SpringerLink
Log in

ORL1 Activation Mediates a Novel ORL1 Receptor Agonist SCH221510 Analgesia in Neuropathic Pain in Rats

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Opioid receptor like 1 (ORL1) receptor activation displayed an anti-nociceptive effect at spinal level for acute and neuropathic pain. SCH221510, an orally active non-peptide ORL1 agonist, was reported to be effective in treating neuropathic pain. The present study used ORL1 antagonist and siRNA to investigate that ORL1 activation mediates intrathecal SCH221510 analgesia in neuropathic pain induced by chronic constrictive injury (CCI) to rat sciatic nerve. Paw withdrawal latency and 50% mechanical threshold were measured for thermal and mechanical hypersensitivity in rats. CCI significantly decreased paw withdrawal latency and mechanical threshold. SCH221510 (3, 10, 30 μg) or ORL1 antagonist ([Nphe1]nociceptin(1-13)NH2, 10 μg) was intrathecally injected to test the behavioral effects on neuropathic pain. Intrathecal siRNA was started on 1 day before CCI surgery and maintained for 7 days. L4-L5 spinal cord ORL1 mRNA and protein were measured by real-time PCR and Western blot. The effect of intrathecal siRNA on SCH2210510 was tested in CCI rats on day 7. Intrathecal SCH221510 dose-dependently reduced thermal and mechanical hypersensitivity induced by CCI. [Nphe1]nociceptin(1-13)NH2 blocked SCH221510 analgesia in CCI rats. Intrathecal siRNA blocked ORL1 mRNA and protein increase induced by CCI. Intrathecal ORL1 siRNA did not change thermal and mechanical hypersensitivity induced by nerve injury. Intrathecal siRNA blocked SCH221510 analgesia in neuropathic pain at spinal level. Conclusively, ORL1 activation mediates SCH221510 analgesia in neuropathic pain at spinal level. The results warrant a potential clinically applicable drug in treating neuropathic pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ORL1 :

opioid receptor like 1

CCI:

chronic constrictive injury

N/OFQ:

nociceptin/orphanin FQ

PWL:

paw withdrawal latency

PB:

phosphate buffer

References

  • Baker MD, Chen YC, Shah SU, Okuse K (2011) In vitro and intrathecal siRNA mediated K(V)1.1 knock-down in primary sensory neurons. Mol Cell Neurosci 48:258–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107

    Article  CAS  PubMed  Google Scholar 

  • Bertorelli R, Bastia E, Citterio F, Corradini L, Forlani A, Ongini E (2002) Lack of the nociceptin receptor does not affect acute or chronic nociception in mice. Peptides 23:1589–1596

    Article  CAS  PubMed  Google Scholar 

  • Briscini L, Corradini L, Ongini E, Bertorelli R (2002) Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury. Eur J Pharmacol 447:59–65

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Sommer C (2006) Nociceptin and its receptor in rat dorsal root ganglion neurons in neuropathic and inflammatory pain models: implications on pain processing. J Peripher Nerv Syst 11:232–240

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Sommer C (2007) Activation of the nociceptin opioid system in rat sensory neurons produces antinociceptive effects in inflammatory pain: involvement of inflammatory mediators. J Neurosci Res 85:1478–1488

    Article  CAS  PubMed  Google Scholar 

  • Cohen SP, Mao J (2014) Neuropathic pain: mechanisms and their clinical implications. BMJ 348:f7656

    Article  PubMed  Google Scholar 

  • Courteix C, Coudore-Civiale MA, Privat AM, Pelissier T, Eschalier A, Fialip J (2004) Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain. Pain 110:236–245

    Article  CAS  PubMed  Google Scholar 

  • Cremeans CM, Gruley E, Kyle DJ, Ko MC (2012) Roles of mu-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates. J Pharmacol Exp Ther 343:72–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149–158

    Article  CAS  PubMed  Google Scholar 

  • deGroot JF, Coggeshall RE, Carlton SM (1997) The reorganization of mu opioid receptors in the rat dorsal horn following peripheral axotomy. Neurosci Lett 233:113–116

    Article  CAS  PubMed  Google Scholar 

  • Dowell D, Haegerich TM, Chou R (2016) CDC guideline for prescribing opioids for chronic pain - United States, 2016. MMWR Recomm Rep 65:1–49

    Article  PubMed  Google Scholar 

  • Faber ES, Chambers JP, Evans RH, Henderson G (1996) Depression of glutamatergic transmission by nociceptin in the neonatal rat hemisected spinal cord preparation in vitro. Br J Pharmacol 119:189–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K (2010) Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships. Bioorg Med Chem 18:7675–7699

    Article  CAS  PubMed  Google Scholar 

  • Houtani T, Nishi M, Takeshima H, Sato K, Sakuma S, Kakimoto S, Ueyama T, Noda T, Sugimoto T (2000) Distribution of nociceptin/orphanin FQ precursor protein and receptor in brain and spinal cord: a study using in situ hybridization and X-gal histochemistry in receptor-deficient mice. J Comp Neurol 424:489–508

    Article  CAS  PubMed  Google Scholar 

  • Ikeda K, Kobayashi K, Kobayashi T, Ichikawa T, Kumanishi T, Kishida H, Yano R, Manabe T (1997) Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K+ (GIRK) channel. Brain Res Mol Brain Res 45:117–126

    Article  CAS  PubMed  Google Scholar 

  • Ko MC, Naughton NN (2009) Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys. J Pain 10:509–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma F, Xie H, Dong ZQ, Wang YQ, Wu GC (2005) Expression of ORL1 mRNA in some brain nuclei in neuropathic pain rats. Brain Res 1043:214–217

    Article  CAS  PubMed  Google Scholar 

  • Mogil JS, Grisel JE, Zhangs G, Belknap JK, Grandy DK (1996) Functional antagonism of mu-, delta- and kappa-opioid antinociception by orphanin FQ. Neurosci Lett 214:131–134

  • Mogil JS, Pasternak GW (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53:381–415

    CAS  PubMed  Google Scholar 

  • Nishi M, Houtani T, Noda Y, Mamiya T, Sato K, Doi T, Kuno J, Takeshima H, Nukada T, Nabeshima T, Yamashita T, Noda T, Sugimoto T (1997) Unrestrained nociceptive response and disregulation of hearing ability in mice lacking the nociceptin/orphaninFQ receptor. EMBO J 16:1858–1864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obara I, Przewlocki R, Przewlocka B (2005) Spinal and local peripheral antiallodynic activity of Ro64-6198 in neuropathic pain in the rat. Pain 116:17–25

    Article  CAS  PubMed  Google Scholar 

  • Pettersson LM, Sundler F, Danielsen N (2002) Expression of orphanin FQ/nociceptin and its receptor in rat peripheral ganglia and spinal cord. Brain Res 945:266–275

    Article  CAS  PubMed  Google Scholar 

  • Rizzi A, Sukhtankar DD, Ding H, Hayashida K, Ruzza C, Guerrini R, Calo G, Ko MC (2015) Spinal antinociceptive effects of the novel NOP receptor agonist PWT2-nociceptin/orphanin FQ in mice and monkeys. Br J Pharmacol 172:3661–3670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Small KM, Nag S, Mokha SS (2013) Activation of membrane estrogen receptors attenuates opioid receptor-like1 receptor-mediated antinociception via an ERK-dependent non-genomic mechanism. Neuroscience 255:177–190

    Article  CAS  PubMed  Google Scholar 

  • Sobczak M, Mokrowiecka A, Cygankiewicz AI, Zakrzewski PK, Salaga M, Storr M, Kordek R, Malecka-Panas E, Krajewska WM, Fichna J (2014) Anti-inflammatory and antinociceptive action of an orally available nociceptin receptor agonist SCH 221510 in a mouse model of inflammatory bowel diseases. J Pharmacol Exp Ther 348:401–409

    Article  CAS  PubMed  Google Scholar 

  • Standifer KM, Rossi GC, Pasternak GW (1996) Differential blockade of opioid analgesia by antisense oligodeoxynucleotides directed against various G protein alpha subunits. Mol Pharmacol 50:293–298

  • Stanfa LC, Chapman V, Kerr N, Dickenson AH (1996) Inhibitory action of nociceptin on spinal dorsal horn neurones of the rat, in vivo. Br J Pharmacol 118:1875–1877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sukhtankar DD, Zaveri NT, Husbands SM, Ko MC (2013) Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/mu-opioid receptor ligands in mouse models of neuropathic and inflammatory pain. J Pharmacol Exp Ther 346:11–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian JH, Xu W, Fang Y, Mogil JS, Grisel JE, Grandy DK, Han JS (1997) Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat. Br J Pharmacol 120:676–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Truini A (2017) A review of neuropathic pain: from diagnostic tests to mechanisms. Pain Ther 6:5–9

    Article  PubMed  PubMed Central  Google Scholar 

  • Varty GB, Lu SX, Morgan CA, Cohen-Williams ME, Hodgson RA, Smith-Torhan A, Zhang H, Fawzi AB, Graziano MP, Ho GD, Matasi J, Tulshian D, Coffin VL, Carey GJ (2008) The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510). J Pharmacol Exp Ther 326:672–682

    Article  CAS  PubMed  Google Scholar 

  • Wang JL, Zhu CB, Cao XD, Wu GC (1999) Distinct effect of intracerebroventricular and intrathecal injections of nociceptin/orphanin FQ in the rat formalin test. Regul Pept 79:159–163

    Article  CAS  PubMed  Google Scholar 

  • Xu M, Aita M, Chavkin C (2008) Partial infraorbital nerve ligation as a model of trigeminal nerve injury in the mouse: behavioral, neural, and glial reactions. J Pain 9:1036–1048

    Article  PubMed  PubMed Central  Google Scholar 

  • Zajac JM, Lombard MC, Peschanski M, Besson JM, Roques BP (1989) Autoradiographic study of mu and delta opioid binding sites and neutral endopeptidase-24.11 in rat after dorsal root rhizotomy. Brain Res 477:400–403

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Thanks Fei Liu for editing the manuscript.

Availability of Data and Materials

The authors will provide data upon request.

Funding

The study was funded by the Xinxiang Central Hospital Startup fund.

Author information

Authors and Affiliations

  1. Department of Neurology, Xinxiang Central Hospital, 56 Jin Hui Da Street, Xinxiang, 453000, Henan, China

    Qiang Wu

  2. Department of Neurology, Luoyang First People’s Hospital, Luoyang, 471000, Henan, China

    Li Liu

Authors
  1. Qiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QW designed the experiment, carried out the study, and drafted the manuscript. LL carried out the experiments.

Corresponding author

Correspondence to Qiang Wu.

Ethics declarations

Ethics Approval

The experiment was approved by the Animals Care and Use Committee of Luoyang Medical College.

Consent for Publication

The authors have consent to publish the study.

Competing Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Q., Liu, L. ORL1 Activation Mediates a Novel ORL1 Receptor Agonist SCH221510 Analgesia in Neuropathic Pain in Rats. J Mol Neurosci 66, 10–16 (2018). https://doi.org/10.1007/s12031-018-1140-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-018-1140-0

Keywords

Search

Navigation