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Systemic administration of WY-14643, a selective synthetic agonist of peroxisome proliferator activator receptor-alpha, alters spinal neuronal firing in a rodent model of neuropathic pain.
Scand J Pain. 2015 Oct 01; 9(1):42-48.SJ

Abstract

Background and aims The clinical management of chronic neuropathic pain remains a global health challenge. Current treatments are either ineffective, or associated with unwanted side-effects. The development of effective, safe therapies requires the identification of novel therapeutic targets using clinically relevant animal models of neuropathic pain. Peroxisome proliferator activated receptor alpha (PPARα), is a member of the nuclear hormone family of transcription factors, which is widely distributed in the peripheral and central nervous systems. Pharmacological studies report antinociceptive effects of PPARα agonists following systemic administration in rodent models of neuropathic pain, however the neuronal mechanisms and sites of action mediating these effects are unclear. The aim of this study was to investigate the effects of systemic administration of the synthetic PPARα agonist, WY-14643 on mechanically-evoked responses of spinal cord dorsal horn wide dynamic range (WDR) neurones in the spinal nerve ligated (SNL) model of neuropathic pain in rats. In addition, comparative molecular analysis of mRNA coding for PPARα and PPARα protein expression in the spinal cord of sham-operated and neuropathic rats was performed. Methods Lumbar L5-L6 spinal nerve ligation was performed in male Sprague-Dawley rats (110-130 g) under isoflurane anaesthesia. Sham controls underwent similar surgical conditions, but without ligation of the L5-L6 spinal nerves. Hindpaw withdrawal thresholds were measured on the day of surgery -day 0, and on days- 2, 4, 7, 10 and 14 post-surgery. At day 14 extracellular single-unit recordings of spinal (WDR) dorsal horn neurons were performed in both sham and SNL neuropathic rats under anaesthesia. The effects of intraperitoneal (i.p.) administration of WY-14643 (15 and 30 mg/kg) or vehicle on evoked responses of WDR neurons to punctate mechanical stimulation of the peripheral receptive field of varying bending force (8-60 g) were recorded. In a separate cohort of SNL and sham neuropathic rats, the expression of mRNA coding for PPARα and protein expression in the ipsilateral and contralateral spinal cord was determined using quantitative real time polymerase chain reaction (qRT-PCR) and western blotting techniques respectively. Results WY-14643 (15 and 30mg/kg i.p.) rapidly attenuated mechanically evoked (8, 10 and 15g) responses of spinal WDR neurones in SNL, but not sham-operated rats. Molecular analysis revealed significantly increased PPARα protein, but not mRNA, expression in the ipsilateral spinal cord of SNL, compared to the contralateral side in SNL rats. There were no changes in PPARα mRNA or protein expression in the sham controls. Conclusion The observation that levels of PPARα protein were increased in ipsilateral spinal cord of neuropathic rats supports a contribution of spinal sites of action mediating the effects of systemic WY-14643. Our data suggests that the inhibitory effects of a PPARα agonist on spinal neuronal responses may account, at least in part, for their analgesic effects of in neuropathic pain. Implication Selective activation of PPARα in the spinal cord may be therapeutically relevant for the treatment of neuropathic pain.

Authors+Show Affiliations

School of Life Sciences, University of Nottingham Medical School, Queens Medical Centre, NG7 2UH, Nottingham, UK. Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, University Road, Galway, Ireland.School of Life Sciences, University of Nottingham Medical School, Queens Medical Centre, NG7 2UH, Nottingham, UK.School of Life Sciences, University of Nottingham Medical School, Queens Medical Centre, NG7 2UH, Nottingham, UK.School of Life Sciences, University of Nottingham Medical School, Queens Medical Centre, NG7 2UH, Nottingham, UK.School of Life Sciences, University of Nottingham Medical School, Queens Medical Centre, NG7 2UH, Nottingham, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29911649

Citation

Okine, Bright N., et al. "Systemic Administration of WY-14643, a Selective Synthetic Agonist of Peroxisome Proliferator Activator Receptor-alpha, Alters Spinal Neuronal Firing in a Rodent Model of Neuropathic Pain." Scandinavian Journal of Pain, vol. 9, no. 1, 2015, pp. 42-48.
Okine BN, Spicer C, Millns P, et al. Systemic administration of WY-14643, a selective synthetic agonist of peroxisome proliferator activator receptor-alpha, alters spinal neuronal firing in a rodent model of neuropathic pain. Scand J Pain. 2015;9(1):42-48.
Okine, B. N., Spicer, C., Millns, P., Bennett, A., & Chapman, V. (2015). Systemic administration of WY-14643, a selective synthetic agonist of peroxisome proliferator activator receptor-alpha, alters spinal neuronal firing in a rodent model of neuropathic pain. Scandinavian Journal of Pain, 9(1), 42-48. https://doi.org/10.1016/j.sjpain.2015.06.004
Okine BN, et al. Systemic Administration of WY-14643, a Selective Synthetic Agonist of Peroxisome Proliferator Activator Receptor-alpha, Alters Spinal Neuronal Firing in a Rodent Model of Neuropathic Pain. Scand J Pain. 2015 Oct 1;9(1):42-48. PubMed PMID: 29911649.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Systemic administration of WY-14643, a selective synthetic agonist of peroxisome proliferator activator receptor-alpha, alters spinal neuronal firing in a rodent model of neuropathic pain. AU - Okine,Bright N, AU - Spicer,Clare, AU - Millns,Paul, AU - Bennett,Andrew, AU - Chapman,Victoria, Y1 - 2015/10/01/ PY - 2015/05/25/received PY - 2015/06/14/accepted PY - 2018/6/19/entrez PY - 2018/6/19/pubmed PY - 2018/6/19/medline KW - Allodynia KW - Neuropathic pain KW - PPAR-α KW - Spinal KW - WY-14643 KW - Wide dynamic range neurones SP - 42 EP - 48 JF - Scandinavian journal of pain JO - Scand J Pain VL - 9 IS - 1 N2 - Background and aims The clinical management of chronic neuropathic pain remains a global health challenge. Current treatments are either ineffective, or associated with unwanted side-effects. The development of effective, safe therapies requires the identification of novel therapeutic targets using clinically relevant animal models of neuropathic pain. Peroxisome proliferator activated receptor alpha (PPARα), is a member of the nuclear hormone family of transcription factors, which is widely distributed in the peripheral and central nervous systems. Pharmacological studies report antinociceptive effects of PPARα agonists following systemic administration in rodent models of neuropathic pain, however the neuronal mechanisms and sites of action mediating these effects are unclear. The aim of this study was to investigate the effects of systemic administration of the synthetic PPARα agonist, WY-14643 on mechanically-evoked responses of spinal cord dorsal horn wide dynamic range (WDR) neurones in the spinal nerve ligated (SNL) model of neuropathic pain in rats. In addition, comparative molecular analysis of mRNA coding for PPARα and PPARα protein expression in the spinal cord of sham-operated and neuropathic rats was performed. Methods Lumbar L5-L6 spinal nerve ligation was performed in male Sprague-Dawley rats (110-130 g) under isoflurane anaesthesia. Sham controls underwent similar surgical conditions, but without ligation of the L5-L6 spinal nerves. Hindpaw withdrawal thresholds were measured on the day of surgery -day 0, and on days- 2, 4, 7, 10 and 14 post-surgery. At day 14 extracellular single-unit recordings of spinal (WDR) dorsal horn neurons were performed in both sham and SNL neuropathic rats under anaesthesia. The effects of intraperitoneal (i.p.) administration of WY-14643 (15 and 30 mg/kg) or vehicle on evoked responses of WDR neurons to punctate mechanical stimulation of the peripheral receptive field of varying bending force (8-60 g) were recorded. In a separate cohort of SNL and sham neuropathic rats, the expression of mRNA coding for PPARα and protein expression in the ipsilateral and contralateral spinal cord was determined using quantitative real time polymerase chain reaction (qRT-PCR) and western blotting techniques respectively. Results WY-14643 (15 and 30mg/kg i.p.) rapidly attenuated mechanically evoked (8, 10 and 15g) responses of spinal WDR neurones in SNL, but not sham-operated rats. Molecular analysis revealed significantly increased PPARα protein, but not mRNA, expression in the ipsilateral spinal cord of SNL, compared to the contralateral side in SNL rats. There were no changes in PPARα mRNA or protein expression in the sham controls. Conclusion The observation that levels of PPARα protein were increased in ipsilateral spinal cord of neuropathic rats supports a contribution of spinal sites of action mediating the effects of systemic WY-14643. Our data suggests that the inhibitory effects of a PPARα agonist on spinal neuronal responses may account, at least in part, for their analgesic effects of in neuropathic pain. Implication Selective activation of PPARα in the spinal cord may be therapeutically relevant for the treatment of neuropathic pain. SN - 1877-8879 UR - https://www.unboundmedicine.com/medline/citation/29911649/Systemic_administration_of_WY_14643_a_selective_synthetic_agonist_of_peroxisome_proliferator_activator_receptor_alpha_alters_spinal_neuronal_firing_in_a_rodent_model_of_neuropathic_pain_ L2 - https://www.degruyter.com/document/doi/10.1016/j.sjpain.2015.06.004 DB - PRIME DP - Unbound Medicine ER -
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