| Division of Developmental Psychobiology - NYSPI @ Columbia University |
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Opiate Dependence and Tolerance; Nociception and Analgesia |
There
are two overriding themes in the work in this lab. One interest is
how the maturation of neural processes result in unique behavioral
and physiological response to the environment. A second long term
research interest has been in those aspects of neural plasticity that
are unique to immature creatures. Thus we study short and long term
effects of drugs during development and of injury to peripheral tissue
and to spinal cord. We study behavior within a developmental framework
and examine how the maturation of biological systems might cause those
changes in behavior after early insult. Much of the work is aimed
at understanding the immediate effects of drug and injury. This approach
lends itself to the use of a variety of behavioral, anatomical, pharmacological,
and genetic methods, all of which are brought to bear on the biological
question of interest. Below are the areas of long standing interest.
Human infants develop opiate dependence and undergo withdrawal if they are exposed in utero to illicit drugs such as heroin, or to prescribed opiates such as methadone, or when treated with opiates for pain. To devise rational treatments for this abstinence syndrome, and to understand the long term consequences of opiate dependence in the neonate, it is necessary to understand more fully how these drugs act in the neonate. The complexity of the human setting make it impossible to tease apart those factors that are due to opiate use and those that are due to the abuse of other drugs, poor prenatal care, undernutrition, or any of the other complications experienced by the mothers of these children. The first and necessary step in this process, to describe the phenomenology of precipitated withdrawal in infants, has been accomplished. We and others have found that the infant rat and mouse undergo a distinct opiate withdrawal, but that the signs and symptoms experienced by the neonate differ from those suffered by the adult. Nonetheless, the infant in abstinence shows developmentally appropriate behavioral signs of withdrawal, increased crying and a negative affective state. The neuroanatomical substrates of infant withdrawal, however, are mediated by similar structures including the periaqueductal gray of the midbrain, the locus ceruleus, and the nucleus accumbens. Despite the similarities in anatomy, there are differences in the cellular messengers mediating withdrawal in the infant and the adult. Neither acute nor chronic co-treatment with competitive or non-competitive NMDA receptor antagonists reduced withdrawal or tolerance at 7 days of age. However, they did at 14 and 21 days of age. In contrast, NOS inhibitors, the AMPA receptor antagonist (NBQX) and the mGluR Group II receptor agonist (DCG-IV) all attenuated withdrawal dramatically at 7 days. This suggests fundamental differences in the role of glutamate receptors in morphine withdrawal (and tolerance) in the infant than in the adult. Currently we are studying ontogenetic differences in gene expression during withdrawal using gene microarrays. These studies will provide a profile of the changes in gene expression induced by chronic opiates during ontogeny.Nociception and AnalgesiaPain and Analgesia The issue of how noxious stimuli are processed at various levels of the neuroaxis has been the subject of intense study for decades. Significant progress has been made in our understanding of how noxious sensations are perceived, processed and dampened, yet little is known of how pain processing differs between immature and adult organisms. Understanding how pain sensation develops is a necessary first step in the development of appropriate therapeutic interventions to alleviate pain and suffering in the human neonate. How to provide safe and effective analgesia for human infants is problematic because a major class of analgesic drugs, the opiates, acts differently in the infant patient than they do in the adult patient. Furthermore, the relationship of unwanted side effects to therapeutic effects changes with age. Classically, opiates have been known to induce analgesia by acting on the central nervous system and a major part of our work is aimed at understanding how those neural systems function during early development. The full description of changes in nociception, opiate induced antinociception, opioid peptide and receptor regulation will provide important information on the development of opiate induced pain relief in both human infants and adults. We have described the late developing role of the NK-1 (Substance P) receptor in nociception and are currently studying the role of glutamate receptors and their interactions with opiates in studies on non-opioid methods and are also examining the role of various opiates given by different routes of administration. Moreover
there is now convincing evidence that early injury can have long term
consequences for subsequent pain perception. Moreover there seems
to be a critical period of development for these effects to occur.
To understand how this can occur we study gene expression by use of
microarrays to understand changes in gene induction as a function
of noxious input. This is studied both within 24 hours after injury
and later in adulthood as a function of the age of injury. In conjunction with John Houlé and Marion Murray at Drexel Medical Center, we are studying exactly what happens in a damaged nerve cell after its axons are cut, and what happens in that cell when grafts allow it to survive and regrow. It is estimated that 10,000 to 12,000 humans survive catastrophic and permanent spinal cord injury each year. With improved medical care these individuals have a normal life span. Therefore the physical, psychological, and economic costs to both patients and society are vast. While it was once thought that the brain and spinal cord were unable to be repaired recent developments provide a much more optimistic picture. Grafts and transplants of nervous tissue or different cells types that secrete growth factors have shown, at least in animal models, that the damaged spinal cord fibers can regrowth into and through a transplant and restore both sensory and motor abilities. But these repair strategies are incomplete because we know little of what happens in the nerve cells that are damaged and when repair is attempted. The central
questions posed by the research is what happens to a neuron when it
is injured and what happens when interventions allow it to survive
and regrow. That is a complex question because the response of the
cell is complex and changes over time. The numbers of changed genes
can be estimated to be in the thousands and knowledge of how that
many genes change after injury requires specialized technology. Using
microarray technology, we ask the question of what exactly are the
changes in expression of all genes in the neuron over the first couple
of months following injury; repair with peripheral nerve grafts immediately
after injury; and in more chronic lesioned animals.
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