Pre-injury administration of morphine prevents development of neuropathic hyperalgesia through activation of descending monoaminergic mechanisms in the spinal cord in mice

Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan.
Molecular Pain (Impact Factor: 3.53). 02/2005; 1:19. DOI: 10.1186/1744-8069-1-19
Source: PubMed

ABSTRACT The present study examined whether pre-injury administration of morphine can prevent partial sciatic nerve injury-induced neuropathic pain in mice. We observed that pre-injury administration of subcutaneous (s.c.) and intracerebroventricular (i.c.v.) morphine dose-dependently prevented the development of both thermal and mechanical hyperalgesia at 7 days following nerve injury in mice. The pre-injury morphine (s.c.)-induced analgesia was significantly blocked by pretreatment with naloxone injected s.c. or i.c.v., but not i.t., suggesting that systemic morphine produced the pre-emptying effects mainly by acting at the supra-spinal sites. Since it is believed that activation of descending monoaminergic mechanisms in spinal cord largely contributes to the supra-spinal analgesic effects of morphine, we investigated the involvement of serotonergic and noradrenergic mechanisms in spinal cord in the pre-injury morphine-induced analgesic effects. We found that pre-injury s.c. morphine-induced analgesic effect was significantly blocked by i.t. pretreatment with serotonergic antagonist, methysergide and noradrenergic antagonist, phentolamine. In addition, pre-injury i.t. injection of serotonin uptake inhibitor, fluoxetine and alpha2-adrenergic agonist, clonidine significantly prevented the neuropathic hyperalgesia. We next examined whether pre-injury morphine prevented the expression of neuronal hyperactivity markers such as c-Fos and protein kinase C gamma (PKCgamma) in the spinal dorsal horn. We found that pre-injury administration of s.c. morphine prevented increased expressions of both c-Fos and PKCgamma observed following nerve injury. Similar results were obtained with i.t. fluoxetine and clonidine. Altogether these results suggest that pre-injury administration of morphine might prevent the development of neuropathic pain through activation of descending monoaminergic pain inhibitory pathways.

  • [Show abstract] [Hide abstract]
    ABSTRACT: To detect central neuron activation, expression of the transcription factor Fos and phosphorylation of the protein kinase ERK (pERK) can be visualized by immunocytochemistry. These approaches have been extensively used to quantify the activation of nociceptive neurons in the spinal dorsal horn (DH) following peripheral stimulation in vivo. Here we propose an alternative and simplified in vitro model to investigate Fos and pERK expression based on the stimulation of acutely dissected spinal cord slices to mimic acute inflammatory changes in DH. Transverse slices were obtained from postnatal (P8-P12) CD1 mice and were treated for 5 min with capsaicin (CAP, 2 μM). CAP induces a strong release of glutamate from primary afferent terminals which, in turn, excites spinal DH neurons. Since ERK phosphorylation and Fos expression occur following different time frames, two distinct protocols were used to detect their activation. Thus, for studying Fos immunoreactivity CAP-treated slices were left for 3 hours in Krebs solution after stimulation. Instead, for studying pERK immunoreactivity slices were maintained in Krebs solution for only 15 min after stimulation. Both Fos and pERK were significantly up-regulated following CAP challenge. To validate our model we tested the efficacy of octreotide (OCT, 1 μM) in preventing the CAP effect on Fos and pERK expression. OCT is a synthetic antinociceptive analogue of somatostatin, one of the neuropeptides involved in the negative modulation of pain signals in DH. After CAP, OCT reduced the response to both Fos and pERK. Our data validate the use of Fos and pERK immunoreactivity in vitro to investigate the activation of spinal nociceptive pathways and testing potentially antinociceptive molecules.
    Annals of anatomy = Anatomischer Anzeiger: official organ of the Anatomische Gesellschaft 01/2013; 196(4). DOI:10.1016/j.aanat.2013.11.005 · 2.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The acute analgesic effect of tramadol has been extensively investigated; however, its long-term effect on neuropathic pain has not been well clarified. In this study, we examined the effects of repeated administration of tramadol on partial sciatic nerve ligation-induced neuropathic pain in rats. Each drug was administered once daily from 0 - 6 days (preventive effect) or 7 - 14 days (alleviative effect) after the surgery. Mechanical allodynia was evaluated just before (preventive or alleviative effect) and 1 h after (analgesic effect) drug administration. Like morphine, first administration of tramadol (20 mg/kg) showed an acute analgesic effect on the developed mechanical allodynia, which was diminished by naloxone. Like amitriptyline, repeated administration of tramadol showed preventive and alleviative effects on the mechanical allodynia that was diminished by yohimbine, but not naloxone. The alleviative effects of tramadol lasted even after drug cessation or in the presence of yohimbine. Repeated administration of tramadol increased the dopamine β-hydroxylase immunoreactivity in the spinal cord. Furthermore, tramadol inhibited the nerve ligation-induced activation of spinal astrocytes, which was reduced by yohimbine. These results suggest that tramadol has both μ-opioid receptor-mediated acute analgesic and α2-adrenoceptor-mediated preventive and alleviative effects on neuropathic pain, and the latter is due to α2-adrenoceptor-mediated inhibition of astrocytic activation.
    Journal of Pharmacological Sciences 02/2014; 124(2). DOI:10.1254/jphs.13223FP · 2.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the spinal cord, PKCγ is an important kinase found in a specific subset of excitatory interneurons in the superficial dorsal horn and in axons of the corticospinal tract (CST). The major interest in spinal PKCγ has been its influences on regulating pain sensitivity but its presence in the CST also indicates that it has a significant role in locomotor function. A hallmark feature of the animal model commonly used to study Multiple Sclerosis, experimental autoimmune encephalolomyelitis (EAE) are motor impairments associated with the disease. More recently, it has also become recognized that EAE is associated with significant changes in pain sensitivity. Given its role in generating pain hypersensitivity and its presence in a major tract controlling motor activity, we set out to characterize whether EAE was associated with changes PKCγ levels in the spinal cord. We show here that EAE triggers a significant reduction in the levels of PKCγ, primarily in the CST. We did not observe any significant changes in PKCγ levels in the superficial dorsal horn but in general the levels tended to be below control levels in this region. In a final experiment we assessed the levels of PKCγ in the spinal cord of EAE mice that had recovered gross locomotor function and compared this to the levels found in EAE mice with chronic deficits. Our findings demonstrate that PKCγ levels are dynamic and that in later stages of the disease, its expression is dependent on the degree of motor function in the model. Taken together these results suggest that PKCγ may be a useful marker in the disease to monitor the status of the CST.
    Journal of neuroimmunology 02/2013; DOI:10.1016/j.jneuroim.2013.01.003 · 2.79 Impact Factor

Preview (3 Sources)

Available from