期刊
JOURNAL OF NEUROSCIENCE
卷 39, 期 33, 页码 6414-6424出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0966-19.2019
关键词
hyperalgesic priming; morphine; opioid-induced hyperalgesia (OIH); protein kinase epsilon (PKC epsilon); toll-like receptor 4 (TLR4)
资金
- National Institutes of Health [NS084545, NS085831]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS085831, R01NS084545] Funding Source: NIH RePORTER
In addition to analgesia, opioids produce opioid-induced hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 m RNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E(2 )hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C epsilon (PKC epsilon) AS-ODN also prevented LDM-induced hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4(+) and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKC epsilon, HDM-induced analgesia, and priming are neither TLR4 nor PKC epsilon dependent. OIH produced by LDM is mediated by both IB4(+ )and peptidergic nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4(+) and peptidergic nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed.
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