Continuous infusion of substance P inhibits acute, but not subacute, inflammatory pain induced by complete Freund’s adjuvant

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Highlights

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    Substance P infusion into the striatum attenuates acute inflammatory pain.

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    Antinociceptive effects of Substance P can be blocked by an NK1 receptor antagonist.

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    Substance P treatment shows no antinociceptive effect in the subacute phase.

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    Substance P treatment does not affect complete Freund’s adjuvant-induced paw edema.

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    Striatal NK1 receptor is downregulated in the subacute phase.

Abstract

Previous studies have reported that continuous infusion with substance P (SP) into rat dorsal striatum ameliorated both mechanical allodynia in both formalin-evoked transient inflammatory pain and neuropathic pain models. However, a role of striatal SP in persistent inflammatory pain has not been demonstrated. The current study examined the effect of continuous infusion of SP into the rat dorsal striatum by reverse microdialysis on persistent inflammatory pain induced by complete Freund’s adjuvant (CFA). Intraplantar injection of CFA evoked both mechanical allodynia and paw edema 3 and 7 days post-injection. The continuous infusion of SP ameliorated the CFA-evoked mechanical allodynia, but not paw edema, 3 days after the CFA injection. This antinociceptive effect of SP was partially inhibited by co-infusion with the neurokinin-1 (NK1) receptor antagonist CP96345. Conversely, at 7 days both CFA-evoked mechanical allodynia and paw edema were not affected by SP treatment. To clarify why the effect of SP treatment on CFA-induced pain changed, we evaluated NK1 receptor protein levels at both time points. The NK1 receptor protein level was decreased at 7, but not 3, days post CFA injection. These data suggest that persistent inflammatory pain can downregulate the striatal NK1 receptor. The current study demonstrates that striatal SP-NK1 receptor pathway can exert antinociceptive effect only on the third days of inflammatory pain phase defined as an acute but not the 7 days defined as a subacute.

Introduction

The dorsal striatum is an important brain region for regulation of motor functions. Additionally, recent studies demonstrated that noxious stimulation increases activity of striatal neurons, and treatment with either glutamate, dopamine, or substance P (SP) into dorsal striatum induces antinociceptive effects in several rodent pain models [[1], [2], [3], [4], [5], [6], [7], [8], [9]]. Moreover, patients with stroke involving the dorsal striatum and Parkinson’s disease present radiculopathy, painful dystonia, and symptoms of central chronic pain [[10], [11], [12], [13]]. Thus, the dorsal striatum plays also a crucial role for pain modulation.

Substance P is an undecapeptide synthesized from preprotachykinin-A mRNA and mainly activates the neurokinin-1 (NK1) receptor [14]. Both SP and NK1 receptors were expressed in several central nervous system (CNS) regions such as globus pallidus, spinal dorsal horn, striatum, and substantia nigra [14]. In the spinal dorsal horn, SP is secreted from the central terminals of activated primary sensory neurons to transmit nociceptive information to CNS [14,15]. Conversely, a recent study demonstrated that injection with SP into cerebral ventricles alleviated both mechanical allodynia and heat hyperalgesia in the early phase of carrageenan-induced inflammatory pain, which was prevented by pretreatment with L-733,060, a selective NK1 receptor antagonist [16]. Thus, SP-NK1 receptor pathway in the brain could be involved in endogenous antinociceptive mechanisms. Additionally, recent studies reported that continuous treatment with SP into the dorsal striatum by using reverse microdialysis, but not acute microinjection, attenuated transient inflammatory pain induced by the formalin test and capsaicin test [4,6]. Moreover, this continuous activation of the NK1 receptor also ameliorated chronic neuropathic pain [9]. These results indicate that activation of NK1 receptors in dorsal striatum leads to antinociceptive effect.

This study uses reverse microdialysis to continuously treat with SP into the dorsal striatum. This microdialysis technique provides several advantages; 1) continuous drug delivery, 2) steady-state concentration of drug without nonspecific injection volume effects, and 3) the ability to adjust the diffusion range of drug to target a specific brain region by changing the length of the dialysis probe [4,6,9,17]. Thus, the reverse microdialysis method can be used to mimic physiological neuropeptide transmission in the brain.

Previous studies clarified that continuous SP infusion into the dorsal striatum can attenuate several transient inflammatory pain models [4,6]. However, an antinociceptive effect of SP in persistent inflammatory pain models has not yet been demonstrated. Therefore, in this study we examined the influence of activating the striatal SP system on complete Freund’s adjuvant (CFA)-evoked persistent inflammatory pain in a rat model.

Section snippets

Animals and animal care

Male Wistar rats, 6 weeks of age, were obtained from Shimizu Laboratory Supplies. These rats were individually housed in a temperature-controlled room (22 ± 2 °C) on a 12:12-h light-dark cycle (lights on from 8:00 a.m. to 8:00 p.m.) and allowed free access to food and water. All experiments utilizing animals were conducted in accordance with the ‘Guidelines for the Care and Use of Laboratory Animals’ established by the Japanese Pharmacological Society and procedures were reviewed and approved

CFA evokes hind paw mechanical allodynia

As shown Fig. 1, i.pl. injection with CFA (100 μL) into left hind paw developed the mechanical allodynia. Three and 7 days after the injection, the mechanical withdrawal thresholds were significantly decreased compared with saline-treated rats (Fig. 1). These data suggested that the CFA treatment evokes the persistent inflammatory pain.

Effect of SP infusion into the striatum on CFA-evoked mechanical allodynia and paw edema in rats

Previous studies reported that continuous treatment with SP into the dorsal striatum by reverse microdialysis ameliorated the mechanical allodynia evoked by

Discussion

The current study investigated the role of striatal SP in persistent inflammatory pain using a reverse microdialysis approach. Continuous striatal SP infusion ameliorated mechanical allodynia, but not paw edema, 3 days following i.pl. injection with CFA via NK1 receptor activation. However, 7 days after CFA injection, NK1 receptor levels were decreased in the contralateral striatum, and the SP treatment did not affect the CFA-evoked mechanical allodynia. Thus, the continuous SP treatment did

Declaration of competing interest

The authors declare no financial conflicts of interest.

Acknowledgements

This work was supported by Grant-in-Aid for Scientific Research (C) grant (15K08233). Experiments were carried out using equipment at the Analysis Center for Life Sciences, Hiroshima University, and the Research Center for Molecular Medicine, Faculty of Medicine, Hiroshima University. We thank Peter Morgan, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.

References (29)

  • G.S. Cottrell et al.

    Ubiquitin-dependent down-regulation of the neurokinin-1 receptor

    J. Biol. Chem.

    (2006)
  • J. Mao et al.

    Patterns of increased brain activity indicative of pain in a rat model of peripheral mononeuropathy

    J. Neurosci.

    (1993)
  • A.C. Barceló et al.

    The striatum and pain modulation

    Cell. Mol. Neurobiol.

    (2012)
  • C.M. Li et al.

    Acetylcholine plays an antinociceptive role by modulating pain-induced discharges of pain-related neurons in the caudate putamen of rats

    Neuroreport

    (2014)
    • View full text
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