Abstract
The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10–20 µg), DAMGO (1–2 µg) and U50,488H (25–50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10–20 µg), deltorphin II (1.5–15 µg) and SNC80 (10–20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.
Highlights
Neuropathic pain has been shown in clinical and animal studies to be resistant to alleviation by morphine [1,2,3,4,5], but the mechanism of this effect is unclear
It has been suggested that the lesser effects of morphine on neuropathic pain are due to the reduced number of presynaptic opioid receptors that results from nerve damage-induced degeneration of primary afferent neurons [64,69] besides other effects, like upregulation of the anti-opioid system CCK, and the NMDA receptor-dependent central sensitization, between others
Our study showed that the expression of all types of opioid receptor mRNA in the spinal cord and DRG was decreased in neuropathic pain
Summary
Neuropathic pain has been shown in clinical and animal studies to be resistant to alleviation by morphine [1,2,3,4,5], but the mechanism of this effect is unclear. A reduction in the number of receptors may be a major factor in the reduced efficacy of opioids, it has become clear that many other factors affect the efficacy of morphine. Such factors include heterologous desensitisation between opioid and proinflammatory chemokine receptors via shared G-protein-coupled systems [20], down-regulation of glutamate transporters in glial cells [21] or release of such substances as NO, ATP, excitatory amino acids, prostaglandins, and proinflammatory cytokines from activated glia [22,23,24,25,26,27]. Activated microglia may weaken morphine analgesia by releasing pronociceptive factors, and the administration of minocycline antagonises this weakening [23,46,47]
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