Abstract
Opioids are widely used for pain relief; however, chronic opioid use causes a paradoxical state of enhanced pain sensitivity, termed “Opioid-induced hyperalgesia (OIH).” Despite the clinical importance of OIH, the detailed mechanism by which it enhances pain sensitivity remains unclear. In this study, we tested whether repeated morphine induces a neuronal circuit polarization in the mouse spinal dorsal horn (SDH). Transgenic mice expressing GFP to neurokinin 1 receptor-expressing neurons (sNK1Rn) and GABAergic interneurons (sGABAn) that received morphine [20 mg/kg, once daily for four consecutive days (i.p.)] developed mechanical hypersensitivity. Repeated morphine altered synaptic strengths in the SDH as a specific cell-type but not in a gender-dependent manner. In sNK1Rn and non-tonic firing neurons, repeated morphine treatment significantly increased frequency of spontaneous excitatory postsynaptic current (sEPSC) and evoked EPSC (eEPSC). In addition, repeated morphine treatment significantly decreased evoked inhibitory postsynaptic current (eIPSC) in sNK1Rn. Conversely, in sGABAn and tonic firing neurons, repeated morphine treatment significantly decreased sEPSC frequency and eEPSC, but had no change of eIPSC in sGABAn. Interestingly, repeated morphine treatment significantly decreased neuronal rheobase of sNK1Rn but had no effect on sGABAn. These findings suggest that spinal neuronal circuit polarization maybe the mechanism of OIH and identify a potential therapeutic mechanism to prevent or treat opioid-induced pain.
Highlights
Chronic pain is a significant health problem
We determined whether repeated morphine treatment changes synaptic strength in the spinal dorsal horn (SDH)
We found that changes in synaptic strength were dependent on neuron type in the opioid-induced hyperalgesia (OIH) mouse model
Summary
Chronic pain is a significant health problem. Globally, 1 in 5 adults suffer from pain, and 1 in 10 adults are diagnosed with chronic pain each year (Goldberg and McGee, 2011). Patients who are repeatedly treated with opioids are routinely diagnosed with enhanced acute and/or chronic pain, an exacerbated pain condition known as opioid-induced hyperalgesia (OIH; Angst and Clark, 2006; Chu et al, 2006). Synaptic plasticity in the spinal dorsal horn (SDH) is present in the long-term potentiation (LTP) of spinothalamic tract projection plasticity neurons (Ikeda et al, 2009) and long-term depression (LTD) of GABAergic neurons (GABAn; Bittar et al, 2017). Our recent studies revealed differential synaptic plasticity between spinothalamic tract projection neurons and GABAn in SDH of spinal nerve ligation mouse model (Kim et al, 2015; Bittar et al, 2017). Synaptic response of spinal NK1Rn to afferent inputs increases with disinhibition (Torsney and MacDermott, 2006)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
