Morphine is one of the most frequently prescribed analgesics for the treatment of neuropathic pain after a spinal cord injury (SCI). Despite widespread use, there has been very little research on the secondary consequences of morphine administration in a spinal injury model. Unfortunately, our research suggests that the acute administration of morphine after SCI has secondary effects that reduce recovery of locomotor function, exacerbate neuropathic pain symptoms, and increase lesion size in the chronic phase of a contusion injury. These data underscore the need for further research on the effects of opioids in a SCI model. To address this issue, we will investigate the molecular consequences of morphine administration after a spinal contusion injury.
Three aims are proposed. First, we will examine the role of spinal processes using agonists and antagonists (co-administered with intrathecal morphine) for classic and non-classic opioid receptors. In other models, three receptor systems have been implicated in the direct effects of morphine, including a) the m- opioid receptor, b) the k-opioid receptor, and c) non-classic opioid receptors on glia. The experiments proposed here aim to directly investigate the contribution of these receptor systems, and the role of 'overexcitation'of neural circuitry, in the morphine-induced attenuation of function after SCI. Our working hypothesis is that morphine produces antinociception (pain inhibition) through activation of classic m-opioid receptors on neurons. At compromised spinal loci, however, activation of k-opioid and glial non-classic opioid receptors may potentiate inflammatory responses and overexcitation, intrinsic to the acute phase of spinal injury, and undermine the plasticity of the neural system as well as increase cell death. Secondly, we aim to modulate spinal molecular changes, to protect functional recovery, while using a clinically relevant systemic route of morphine administration to produce analgesia. We hypothesize that we can block the effects of morphine at the spinal level using k-opioid receptor antagonists, or minocycline to block non-classic opioid activation of glia. We will also test the effects of overexcitation by blocking spinal NMDA receptor function with MK-801. Finally, we will identify cellular changes inherent to the contusion injury itself, and those produced though activation of classic and/or non-classic opioid receptors. For this third aim, we plan to target specific receptor systems, and use a cluster analysis to ascertain which molecular end-points co-vary with specific consequences of morphine administration. This proposal innovatively couples modern discoveries in opioid pharmacology with research on spinal cord injury. Most importantly, it will allow us to identify pharmacological interventions that block the adverse effects of opioids at a spinal level, while increasing morphine's beneficial (antinociceptive) effects after SCI.

Public Health Relevance

Morphine undermines recovery of function after SCI: Deriving molecular mechanisms Project Narrative Morphine is one of the most effective and most commonly prescribed analgesics for the treatment of neuropathic pain after a spinal cord injury (SCI). Unfortunately, however, recent research suggests that morphine may have adverse secondary effects after SCI, attenuating the recovery of locomotor function, increasing tissue loss, and producing symptoms of paradoxical pain in the chronic stages of injury. To improve the safety and analgesic efficacy of opioids used after SCI, the proposed experiments will 1) identify critical molecular changes that underlie morphine's effects, 2) use pharmacological manipulations to block adverse effects (reduced recovery, tissue loss) at a spinal level, and potentiate morphine's beneficial (analgesic) effects, and 3) further understanding of the causal molecular mechanisms in neuropathic pain.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Pilotte, Nancy S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas A&M University
Schools of Arts and Sciences
College Station
United States
Zip Code
Maldonado-Bouchard, Sioui; Peters, Kelsey; Woller, Sarah A et al. (2016) Inflammation is increased with anxiety- and depression-like signs in a rat model of spinal cord injury. Brain Behav Immun 51:176-95
Aceves, M; Mathai, B B; Hook, M A (2016) Evaluation of the effects of specific opioid receptor agonists in a rodent model of spinal cord injury. Spinal Cord 54:767-777
Grau, James W; Huie, J Russell; Lee, Kuan H et al. (2014) Metaplasticity and behavior: how training and inflammation affect plastic potential within the spinal cord and recovery after injury. Front Neural Circuits 8:100
Luedtke, Kelsey; Bouchard, Sioui Maldonado; Woller, Sarah A et al. (2014) Assessment of depression in a rodent model of spinal cord injury. J Neurotrauma 31:1107-21
Garraway, Sandra M; Woller, Sarah A; Huie, J Russell et al. (2014) Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis. Pain 155:2344-59
Woller, Sarah A; Malik, Jamal S; Aceves, Miriam et al. (2014) Morphine self-administration following spinal cord injury. J Neurotrauma 31:1570-83
Strickland, Eric R; Woller, Sarah A; Hook, Michelle A et al. (2014) The association between spinal cord trauma-sensitive miRNAs and pain sensitivity, and their regulation by morphine. Neurochem Int 77:40-9
Woller, Sarah A; Hook, Michelle A (2013) Opioid administration following spinal cord injury: implications for pain and locomotor recovery. Exp Neurol 247:328-41
Woller, Sarah A; Moreno, Georgina L; Hart, Nigel et al. (2012) Analgesia or addiction?: implications for morphine use after spinal cord injury. J Neurotrauma 29:1650-62