Environmental influences found to have role for development and function of the pain system

Contrary to previous assumptions, recent findings indicate that experience-dependent mechanisms have a fundamental role for the proper development and function of the pain system.

Tactile, or touch, information now appears to play a fundamental role in guiding the functional maturation of the pain sensitivity system during normal development. This explains how the pain system can be functionally adapted despite the rare occurrence of noxious stimuli during development. Maintained input over “pain” fibers after injury may instead perturb normal development and cause long-term maladaptive changes in somatosensory and pain processing. Developmental mechanisms thus determine the structure and synaptic strengths in the “pain” transmission system.

Scientists now know that synaptic strength can also be modified for prolonged periods of time in the adult following injury, trauma, or inflammation, likely contributing to phenomena such as hyperalgesia and allodynia, namely exacerbated pain in response to painful stimuli, and pain in response to normally innocuous stimuli, respectively. A symposium at this meeting will summarize recent breakthroughs on the experience-dependent mechanisms that determine the adult organization of spinal pain systems and pain sensitivity.

Touch input guides the normal maturation of the pain system, says Professor Jens Schouenborg, MD, of the University of Lund in Sweden, chair of the symposium. “The organization of the pain system has for a long time been assumed to be essentially innate, i.e., to develop independently of experience. However, several recent findings instead indicate that the pain system undergoes profound experience-dependent reorganization during development,” says Schouenborg.

Using computer modeling and behavioral experiments, Schouenborg and his colleagues report that tactile feedback ensuing on spontaneous muscle twitches during sleep has a key role in guiding the functional adaptation of the spinal pain reflex networks during development. The basic concept is that spinal interneurons, grouped in modules, spontaneously start up muscle twitches that, in turn, cause a sensory feedback informing about the consequence of the resulting movement pattern. This sensory feedback is then “imprinted” on the circuitry of the module.

In a sense, the spinal module asks the question “What function do I have?” and then receives a sensory echo answering the question. The strength of the connections in the circuitry can then be set appropriately. That tactile (i.e., innocuous), rather than noxious, (i.e., painful) input is used to set the gain in the pain pathways solves the puzzle of how pain systems can be functionally adapted during early life despite the rare occurrence of noxious stimuli.

In one study, the authors examined the development of a withdrawal reflex in 161 rats after a brief noxious heat stimulus to the tail. Tail withdrawal movements were erroneous in more than 50 percent of the cases up to approximately postnatal day 10. Thereafter, tail movements gradually become appropriate and reached adult levels (i.e., less than 10% error) at postnatal day 21. Interestingly, this adaptation occurred even when the tail was deprived of any noxious stimuli by either encasement in a tube or application of topical anesthetics.

However, removal of tail hairs to prevent tactile sensation blocked pain responses and adaptation, indicating that low-threshold mechanoreceptors are necessary for adaptation to the noxious stimulus. Anesthetizing the tail in adult rats did not alter the reflex. These findings indicate that this cross-modality adaptive response during early development is driven by normally activated mechanosensors that influence the strength of synapses involved in the withdrawal reflex. It seems in this case, “no pain, no gain” is not the operating principle. In another animal study, it was demonstrated that touch feedback on spontaneous twitches during the postnatal days 12 to 17 alter the pain related withdrawal reflex.

The results also provide a key to understanding the more general problem of how the body constitution is represented in the CNS and highlight the role of fetal movements in this respect. It is envisioned that knowledge about the cellular mechanisms underlying the discovered self-organizing mechanism will allow artificial down regulation of pain sensitivity and thereby open up for the development of new therapeutic methods to relieve chronic pain.

Scientists also have found that long-term changes occur in spinal connectivity following neonatal noxious stimulation.

More than ten percent of babies in the US and UK are born prematurely and many have to undergo surgery and intensive care soon after birth, notes Maria Fitzgerald, PhD, of University College of London.

“The nervous system in these infants is still immature and clinical studies have suggested that early pain related to such interventions in premature babies can have long-term consequences upon pain behavior and perception in later life,” says Fitzgerald. Until now, little was known about how this might occur.

Fitzgerald and her colleagues have found that that early pain and skin injury at birth changes the properties of sensory neurons in the spinal cord so that they become permanently more ’receptive’ to skin stimulation, long after the original wound and pain have gone. Such increased neuronal responsiveness may lead to abnormal sensations in the adult.

In basic neurobiology studies carried out on infant rats, pups had a local skin injury to one hindpaw at birth (under anesthetic) and were then left to grow up normally in their litters for six weeks. They were then anesthetized again and using electrophysiological techniques, neuronal activity in response to touch and pressure of the originally wounded skin area was recorded from the sensory neurons in their spinal cord. The properties of sensory neurons in the spinal cord were different from control animals, in that the receptive fields, that is, the area of skin that when stimulated excites sensory neurons, were significantly larger than controls.

In order to prevent such changes from occurring, scientists need to understand the basis for their development. It is known that the normal formation of neural connections in the developing brain requires a fine balance of electrical activity between cells. If this balance is disrupted, connections are lost and abnormal ones are formed. Fitzgerald has demonstrated the importance of neural activity triggered by the neurotransmitter glutamate acting on NMDA receptors, in the formation of sensory connections in the newborn spinal cord.

Treating the newborn spinal cord with very low doses of NMDA receptor blocker during a critical period of early life mimics the effects of early skin injury and leaves the sensory neurons more ’receptive’ to skin stimulation when adult. The NMDA experiments suggest, as has been shown in other areas of sensory nervous system development, that the pattern and level of background sensory neural activity is critical for normal skin sensory development. Early skin injury may cause abnormal or unbalanced neural activity at a critical stage of development, leading to an altered set of central sensory connections. Clearly, more work is needed in this area but this data demonstrates the potential clinical importance of neonatal plasticity, learning, and memory in pain development.

Underlying such memories of painful events are specific cellular mechanisms, notes Jürgen Sandkühler, MD, PhD, of the Vienna University Brain Research Institute in Austria.

The central nervous system has an unimaginable complexity and this is a prerequisite for the extremely high performance of the brain, says Sandkühler. Despite the complexity of chronic pain, however, it now appears that a small, but well defined group of neurons in spinal dorsal horn plays a pivotal role for abnormal sensitivity to pain following inflammation or nerve damage.

Sandkühler and his colleagues have shown that subpopulations of these spinal neurons, with different ascending projections to the brain, may become sensitized under pathological conditions. To be more specific, neurons in lamina I of spinal dorsal horn that express the neurokinin 1 receptor for substance P mediate this abnormal pain sensitivity. The cellular mechanisms of these sensitizations resemble those in hippocampus known to be important for cognitive learning and memory. Depending upon the kind of underlying pathology, different spinal neurons become sensitized so that different parts of the CNS “memorize” different aspects of chronic pain.

Results were obtained from more than seven hundred spinal nerve cells in an “in vitro” spinal cord-dorsal root slice preparation from rats. Prior to recordings, animals received an injection of a retrograde tracer into different brain areas. Three days later, spinal neurons with a projection to the injection site were labeled and could thereby be identified in the slice preparation. It is the first time this approach was used in such a spinal cord preparation.

Then a dorsal root was stimulated electrically and C-fiber-evoked responses were recorded from spinal projection neurons. C-fibers are known to transmit pain-related information from the periphery to the spinal cord. After a few control responses, dorsal roots were stimulated with different stimulation patterns which can also be observed in C-fibers during inflammation or nerve injury. After these stimuli, the responses of well-defined subgroups of spinal dorsal horn neurons were much enhanced (up to 300 % above control levels), indicating that pain-related information was amplified strongly.

Depending upon the type and pattern of dorsal root stimulation, different subgroups of spinal projection neurons became sensitized. Other spinal neurons, with no direct projection to the brain and with no neurokinin 1 receptors for substance P but which were also involved in processing pain-related information were, in contrast, not affected. This suggests that enhanced pain sensitivity (hyperalgesia) is processed by a different population of spinal neurons as compared to normal, physiological pain.

Jennifer Laird, PhD, of the pharmaceutical company AstraZeneca in Montreal explains the mechanisms underlying pain evoked by tactile input after peripheral inflammation. She notes that we all have experienced the sensation of pain – injury or damage to body tissue produces an ongoing sensation so that the area hurts in the absence of any external stimulus.

Think of the last time you had a bad sunburn. Sunburnt skin usually hurts even more when you touch it! This is because damaged areas are also hypersensitive to external stimuli. So even light touch or pressure that feels fine when applied to normal skin is painful and unpleasant in the damaged area. This is the body’s way of making you slow down and protect the injured area so that it has a chance to heal. Both the ongoing pain sensation and the hypersensitivity usually fade and disappear as the injury heals, but can last days or weeks and in patients with chronic pain, for years.

So how does the nervous system responsible for keeping the brain informed about touch or painful stimuli applied to that part of the body “remember” that the injury occurred? Laird has found that neurons in the central nervous system, in the spinal cord – where sensory information from the body is first processed – do “remember” a peripheral injury even when isolated and maintained in vitro.

The spinal cord was isolated from control rats and rats with an experimental inflammation of one paw. The spinal cord was maintained in vitro and the responses of the nociceptive circuitry analyzed by electrophysiologically recording reflex responses to electrical stimulation of the afferent nerve fibers that had innervated the injured tissue. Spinal preparations obtained from rats with an injured paw showed greatly enhanced neuronal responses compared with those obtained from control rats.

Laird also has described how the intracellular signaling pathways and molecular mechanisms known to be critical for classical learning and retention of memories in the hippocampus seem to be involved in spinal “memories” of painful injury.

The scientists have shown in both rats and mice that extracellular signaling-related kinases are activated in the spinal cord by painful stimuli with a time course that matches the maintenance of hypersensitivity. The activated kinases translocate to the neuronal nuclei, thereby enabling an influence on gene expression. Blockers of this activation dose-dependently reduce the hypersensitivity observed in behavioral tests in mice.

The results also provide a key to understand the more general problem of how the body constitution is represented in the CNS. It is envisioned that knowledge about the cellular mechanisms underlying the storage of painful events will allow artificial down regulation of pain sensitivity and thereby open up for the development of new therapeutic methods to relieve chronic pain.