Opioids are widely used to treat pain after trauma. Opioid use for pain management has dramatically in- creased, with little assessment of potential negative consequences for ongoing pain. Recent reports are critical of the lack of controlled, long-term studies to support the dramatic escalation of opioid treatment for chronic pain over the past decade. While one long-term concern is that there may be no benefit, another is that opioids could have negative consequences for pain. There would be major implications were opioid treatment to pro- long the course of pain long after opioid cessation. As described in this proposal, robust opioid-induced chroni- fication of pain does indeed occur, making this a phenomenon critical to understand. Disturbingly, we have discovered that opioids given around the time of trauma may be contraindicated: a brief course of treatment with morphine (5 mg/kg b.i.d. for 5-7 days) can amplify the magnitude and duration of neuropathic pain for months thereafter. Strikingly, this deleterious opioid effect occurs across all models tested to date: inflammatory pain, peripheral and central neuropathic pain, and post-operative pain, supportive that this is a widespread phenomenon worthy of study. This unanticipated effect of morphine across time and di- verse pain models had not been previously reported. Beyond our initial studies, nothing is known regard- ing the spinal mechanistic underpinnings of this multi-month exaggeration of neuropathic pain by a brief exposure to morphine restricted to the early post-trauma period.
Three Aims are proposed. All studies are undertaken in both sexes, given that documented male/female differences in immune and glial function, neuropathic pain, and responses to opioids, suggest that distinct un- derlying mechanisms will likely be found across sexes.
The first Aim examines how a short course of morphine in the early post-trauma period functionally modifies the neuroimmunology of the ipsilateral lumbar dorsal spi- nal cord and discovers which of these changes mediate pain enhancement.
The second Aim utilizes state-of- the-art Robust Activity Marking (RAM) technologies in spinal cord to address how identified mediators of mor- phine-induced pain enhancement align with retrogradely labeled spinothalamic neurons with defined activation state.
The third Aim examines supraspinal mechanisms contributing to morphine-induced chronification of neu- ropathic pain.
Aim 3 utilizes state-of-the-art DREADD reversible inactivation of microglia vs. excitatory neurons to define the role of the caudal granular insular cortex (CGIC), which we have previously shown (in the ab- sence of early post-trauma morphine) to be critical to chronic pain maintenance. Here we will reversibly inhibit, in a cell-type targeted fashion, either microglia or excitatory neurons in CGIC either only during morphine dos- ing or only during the period of morphine-induced chronification of pain to define CGIC involvement in induction versus maintenance of this enhanced neuropathic pain state.
Opioid use for pain management has dramatically increased, with little assessment of potential pathophysio- logical consequences for the primary pain condition. Disturbingly, we have recently discovered (Grace et al., PNAS 2016) that opioids given around the time of trauma may be contra-indicated: a brief course of treatment with morphine (5 mg/kg b.i.d. for 5-7 days) can amplify the magnitude and/or duration of pain for weeks-to- months thereafter, across all animal models studied to date. This proposal seeks to understand the mecha- nisms responsible for the dramatic enhancement of neuropathic pain by early post-trauma morphine.
