Michelle A. Hook, Ph.D. - US grants

DESCRIPTION (provided by applicant): Spinal cord injury affects over a quarter of a million people in the United States alone, with a variety of devastating consequences including loss of bowel, bladder, sexual, and limb function, and neuropathic pain. Considerable research is now focused on finding ways to ameliorate the functional consequences of injury.Surprisingly, however, little is known about the consequences of first-line analgesics on the long-term recovery of motor and sensory function. Opiates are given soon after an injury and are used by a significant proportion of the spinally-injured population, but we do not know what impact they have on functional recovery. The current proposal aims to address this issue. We will look at the functional consequences of repeated morphine exposure after a spinal contusion injury using male, Sprague-Dawley rats. Preliminary data suggests that even a single dose of morphine can have a lasting effect on both sensory function (producing a tactile allodynia) and lesion size. We have also shown that uncontrollable stimulation undermines sensory and motor function, and interacts with morphine treatment, producing an increase in mortality. The proposed experiments will extend this research using a clinically relevant, extended morphine treament regime. Using a wide range of behavioral tests we will compare the motor and sensory recovery of rats given a single injection of morphine, repeated morphine injections (0, 2.5, 5,10, 20 mg/kg), or saline over a 3 week period. Because the consequences of morphine treatment may be most evident in the presence of an environmental challenge, half the subjects in each condition will receive 30 min of uncontrollable stimulation 1 day after injury. Functional recovery will be monitored for 6 weeks. The proposed studies, therefore, will use a 2 (acute vs extended morphine) x 5 (dose) x 2 (shock vs unshock) experimental design to elicidate the functional consequences of morphine. The hypothesis is that extended morphine treatment will undermine recovery. These effects may be most evident after a high dose and in subjects that receive uncontrollable stimulation. This initial study will lay the foundation for many future research projects looking at 1) the molecular mechanisms underlying the effects of morphine, 2) effects of injury variables such as lesion size, and 3) impacts of other first-line analgesics such as NSAIDS, acetaminophen, and gabapentin on the recovery of function after a spinal cord injury.

[unreadable] DESCRIPTION (provided by applicant): The isolated spinal cord is inherently capable of learning about Pavlovian and instrumental relationships. Little is known, however, about the ways in which these two forms of learning may interact. The current studies aim to further knowledge of spinal learning, and also to take our empirical understanding of learning n the cord to a clinical level. Previous studies have shown that uncontrollable electrical stimulation undermines the plasticity of the cord producing an instrumental learning deficit that lasts for up to 48 hrs. Uncontrollable stimulation also undermines the recovery of function after a spinal contusion injury. The aim of this proposal is to examine spinal cord mechanisms that enable, and protect plasticity within the spinal cord. Preliminary results suggest that 'predictability' can protect plasticity in the isolated cord. Rats treated with predictable (Pavlovian) shock are subsequently able to learn an instrumental relationship, whereas unpredictable shock results in the learning deficit. The experiments we propose further examine the interactions between predictability and plasticity. First, we will examine whether establishing a Pavlovian relationship in spinal neurons can immunize or reverse the detrimental effects of uncontrollable electrical stimulation. A Pavlovian relationship will be established by applying a weak shock to the tail (CS) immediately before a stronger shock to the tibialis anterior muscle (US). Rats will be treated with Pavlovian conditioning before or after uncontrollable shock and their capacity to learn will be assessed using an instrumental task. We will then examine neurobiological cascades that modulate plasticity. Preliminary studies suggest that a CS can produce a ?-opioid mediated antinociception, and ? agonists are able to undermine the induction of the instrumental learning deficit produced with uncontrollable shock. The proposed studies will examine whether the protective effects of the CS on plasticity also depend on a ligand that acts on the ? receptor. A ? antagonist (nor BNI, i.t.) will be administered concurrently with the CS to determine whether this undermines the protective effects. Finally, using a variety of motor and sensory assays, we will examine the implications of Pavlovian conditioning for the recovery of function after a contusion injury. An understanding of spinal cord plasticity, how it is disrupted, and how it can be restored, is essential to the development of new procedures that promote recovery after a spinal injury. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): 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.