ABSTRACT
AIM: Neuropathic pain is often refractory to conventional analgesics including opioids and non-steroidal anti-inflammatory drugs. Evidence suggests nicotinic acetylcholine receptor ligands regulate pain transmission. Effects of α4ß2 nicotinic acetylcholine receptor activation on pain behaviours after nerve injury were studied. METHODS: Mice were subjected to partial sciatic nerve ligation (PSL). Nicotinic acetylcholine receptor α4 and ß2 subunits localization in injured nerves were evaluated by immunohistochemistry. Neuropathic pain, assessed by tactile allodynia and thermal hyperalgesia, was examined by von Frey test and Hargreaves test respectively. RESULTS: Nicotinic acetylcholine receptor α4 and ß2 subunits were up-regulated in injured nerves and were expressed on F4/80-positive macrophages. When nicotine was perineurally administered daily for 4 days (day 7-10; maintenance phase) after nerve injury, pain behaviours were significantly alleviated. The inhibitory effects of nicotine were reversed by co-administration of mecamylamine (non-selective nicotinic acetylcholine receptor antagonist) and dihydro-ß-erythroidine (selective α4ß2 nicotinic acetylcholine receptor antagonist). Likewise, when α4ß2 nicotinic acetylcholine receptor agonists (TC2559 or ABT418) were administered daily for 4 days (day 7-10) after nerve injury, pain behaviours were significantly attenuated. On the other hand, nicotine administered daily for 4 days (day 0-3; initiation phase) after nerve injury alleviated pain behaviours, which were antagonized by co-administration of dihydro-ß-erythroidine. TC2559 administered daily for 4 days (day 0-3) also attenuated nerve injury-induced pain behaviours. CONCLUSION: The activation of α4ß2 nicotinic acetylcholine receptor expressed on infiltrating macrophages in injured nerves may participate in the relief of PSL-induced neuropathic pain during maintenance and initiation phases.
Subject(s)
Hyperalgesia/metabolism , Neuralgia/metabolism , Peripheral Nerve Injuries/metabolism , Receptors, Nicotinic/metabolism , Signal Transduction , Analgesics/pharmacology , Animals , Disease Models, Animal , Male , Mice, Inbred C57BL , Neuralgia/diagnosis , Peripheral Nerve Injuries/drug therapy , Sciatic Nerve/drug effects , Sciatic Nerve/metabolism , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Neuropathic pain is caused by neural damage or dysfunction and neuropathic pain-related symptoms are resistant to conventional analgesics. Neuroinflammation due to the cytokine-chemokine network may play a pivotal role in neuropathic pain. We demonstrate that macrophage inflammatory protein-1ß (MIP-1ß) participates in neuropathic pain. METHODS: Mice received partial sciatic nerve ligation (PSL), and tactile allodynia and thermal hyperalgesia were assessed by von Frey test and Hargreaves test, respectively. Agents were administered into the region surrounding the sciatic nerve (SCN). RESULTS: Using reverse transcription polymerase chain reaction, the mRNA expressions of MIP-1ß and its receptor (CC-chemokine receptor 5; CCR5) in the injured SCN were up-regulated after PSL. MIP-1ß immunoreactivity was localized in macrophages and Schwann cells and increased in the injured SCN on day 1. PSL-induced tactile allodynia on days 4 to 7 was prevented by the administration of MIP-1ß neutralizing antibody (anti-MIP-1ß; on days 0, 3 and 6). PSL-induced up-regulations of inflammatory cytokine-chemokine mRNAs in the injured SCN were suppressed with anti-MIP-1ß treatment on day 7. Administration of CCR5 antagonist, D-ala-peptide T-amide (on days 0, 3 and 6) prevented tactile allodynia and thermal hyperalgesia on days 4 to 14. Single administration of recombinant mouse MIP-1ß (rmMIP-1ß) elicited tactile allodynia. Moreover, rmMIP-1ß increased the mRNA expression of inflammatory mediators in the SCN on day 1 after administration. CONCLUSIONS: These results suggest that MIP-1ß is a novel key mediator, and the peripheral MIP-1ß-CCR5 axis contributes to neuropathic pain. Therefore, investigation of this cascade might be a validated approach for the elucidation of neuropathic pain mechanisms.
Subject(s)
Chemokine CCL4/metabolism , Hyperalgesia/metabolism , Peripheral Nerve Injuries/metabolism , RNA, Messenger/analysis , Receptors, CCR5/metabolism , Sciatic Neuropathy/metabolism , Animals , CCR5 Receptor Antagonists , Chemokine CCL4/pharmacology , Macrophages/metabolism , Male , Mice , Mice, Inbred ICR , Neuralgia/metabolism , Peptide T/pharmacology , Peripheral Nerve Injuries/complications , Reverse Transcriptase Polymerase Chain Reaction , Schwann Cells/metabolism , Sciatic Nerve/injuries , Sciatic Neuropathy/etiology , Up-RegulationABSTRACT
Tolerance to morphine analgesia following repeated administration disturbs the continuation of opioid therapy for severe pain. Emerging evidence suggests that the development of morphine tolerance may be antagonized by painful stimuli. To clarify the detailed mechanisms of these phenomena, we examined the effects of several pain stimuli on morphine-induced tolerance. Subcutaneous (s.c.) injection of morphine (10 mg/kg) produced an analgesic effect, which was evaluated by tail-pinch test. Morphine-induced analgesia was diminished by repeated administration of morphine (10 mg/kg, s.c.) once a day for 5 days, demonstrating the development of tolerance. Morphine analgesic tolerance was suppressed by nerve injury-induced neuropathic pain and formalin- or carrageenan-induced inflammatory pain. Tolerance to serum corticosterone elevation by morphine (10 mg/kg), which was evaluated by fluorometric assay, was also suppressed by formalin-induced inflammatory pain. Moreover, morphine analgesia induced by intracerebroventricular (10 nmol) or intrathecal (5 nmol) injection was diminished by repeated administration of morphine s.c., and this was also suppressed by carrageenan-induced inflammatory pain. These results suggest that morphine tolerance is inhibited by several pain stimuli, including neuropathic and inflammatory pain, through central mechanisms.
