Editors' Choicechronic Pain

Fire extinguishers turn down the gain on pain

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Science Translational Medicine  22 Jun 2016:
Vol. 8, Issue 344, pp. 344ec98
DOI: 10.1126/scitranslmed.aag2109

Although opiates are very effective in treating acute pain, their benefits are limited in chronic pain by the development of tolerance and opioid-induced hyperalgesia (OIH). OIH is a paradoxical state of heightened sensitivity to painful stimuli that is caused by opiates and unrelated to the original source of pain. Although tolerance can be overcome by increasing the dose of opiates, more medication can worsen pain in OIH. A better understanding of the mechanisms of OIH could lead to treatments to block the sensitizing actions of opiates. In a model of chronic neuropathic pain, Grace et al. provide a link between OIH and NLRP3 inflammasome-dependent production of interleukin-1β (IL-1β) in microglia with therapeutic implications.

The investigators used constriction of the sciatic nerve to model chronic neuropathic pain in rats, followed by a short, 5-day course of subcutaneous morphine equivalent to a moderate dose in humans. Pain responses were exaggerated and prolonged by morphine. Using pharmacologic and genetic approaches, the authors showed that morphine increased pain sensitivity through TLR4, leading to activation of the NLRP3 inflammasome and resultant caspase-1–dependent activation of IL-1β, a cytokine previously known to contribute to OIH. Immunohistochemistry of NLRP3 and the microglial marker Iba1, coupled with inhibition of sensitization by in vivo transfection of a Designer Receptor Exclusively Activated by a Designer Drug (DREADD) under a CD68 promoter, localized this pathway to dorsal spinal microglia.

Consistent with prior reports, intrathecal infusion of IL-1ra to block IL-1β, TB-2-081 to block IL-6, or etanerecpt to block TNF (the latter two are both regulated by IL-1β) prevented and treated morphine-induced hyperalgesia. This study also showed down-regulation by morphine of spinal microRNA miR-223, a negative regulator of NLRP3, suggesting that delivery of exogenous miR-223 is another therapeutic avenue to explore. Major challenges in extension of these results to humans are the longer duration of pain compared with what was modeled in the rats, the various types and doses of clinically available opiates, and the effects of genetic polymorphisms. Nonetheless, these challenges must be overcome to turn down the gain on pain.

P. M. Grace et al., Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc. Natl. Acad. Sci. U.S.A. 113, E3441–E3450 (2016). [Abstract]

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