Nociceptive Mechanisms

Physical or chemical impacts that have the potential to induce tissue damages induce withdrawal reflex together with immediate development of pain experience. If the withdrawal reflex prevents tissue damage, the pain ceases within seconds. This type of pain is absolutely essential for survival.

In the case of tissue damage, a qualitatively and quantitatively different pain experience develops; tissue injury-associated pain persists until the tissue integrity is restored and it is characterised by “pathological” sensory experiences including hypersensitivities to mechanical and thermal stimuli. Tissue injury-associated pain is a fundamental component of the adaptive response of our body to restore tissue integrity as it discourages the use of the injured tissues thus reduces the probability of further damages.

Serious injuries however, often lead to unbearable pain. Further, pain is often disproportionate with the injury. Finally pain persists when healing is not possible, or it may do so even after an apparently completed healing. In these cases pain has no benefit, as it does not serve any biological function. Instead, pain in these cases is considered maladaptive and a disease on its own. Current analgesic measures often fail to provide satisfactory pain relief in such conditions or induce undesirable, often serious and life-threatening, effects. Therefore, novel analgesics must be developed and/or the analgesic specificity of current approaches must be significantly improved.

The development and persistence of tissue injury-associated pain depend on a series of molecular changes in cells of the neuronal pathways, which are involved in processing information on painful stimuli (nociceptive pathways). Pain-sensing primary sensory neurons constitute the first neurons in that pathway and they exhibit the first set of changes in molecular composition following the activation by agents found in the injured tissues. If sensory nerve fibers are also injured, injury-induced signals in primary sensory neurons also contribute to, or in fact might be the only source for inducing, the molecular changes. Molecular changes in primary sensory neurons lead to use-dependent increases in the activity and responsiveness (sensitization) of the cells. The increased activity of primary sensory neurons then drives molecular changes and subsequent sensitisation in spinal dorsal horn cells that form the first central nervous system circuitries, which have a decisive role in allowing the nociceptive information to enter the brain where the pain experience develops.

The analytical technologies we use allow us to elucidate tissue injury-induced molecular changes in the injured tissues, primary sensory neurons and spinal dorsal horn cells, and map the tissue injury-associated molecular machineries. With further analysis, pivotal molecules for the function of those molecular machineries are identified. The traditional approaches we use finally allow us to verify the suitability of the pivotal molecules for the development of novel therapies to control pain associated with tissue injuries.

Our research activity is driven by the unmet medical need to provide satisfactory control of pain associated with tissue damage. The lack of sufficient and safe control of tissue injury-associated pain leads to suffering for patients and families, has devastating effects on the quality of life and constitutes a significant financial burden to health care providers, the economy and society. Therefore, finding new targets for therapies aiming to provide satisfactory and safe control of pain is of imperative importance.

Tissue injury-associated pain is one of the cardinal components of the adaptive measure of the inflammatory reaction that inevitably follows the injury. Molecules released from the injured tissues together with molecules produced during the inflammatory reactions are pivotal for inducing molecular changes and subsequent sensitisation in primary sensory neurons. Increased activity of primary sensory neurons then drives sensitisation in nociceptive pathways in the central nervous system.

We are using various injuries and in vitro and in vivo inflammatory pain models to elucidate injury- and inflammation-induced molecular changes in tissues, primary sensory neurons and the spinal dorsal horn. The injuries include burn injury, which is one of the most frequent traumatic injuries affecting ~11 million people annually worldwide. Burn injury is characterised by severe tissue damage and inflammatory response. Further, pain associated with a burn injury is considered the most excruciating people can experience. Finally, pain following burn injury often persists after healing. Therefore, we are using, among others, burn tissues (e.g. skin biopsies from burn-injured patients) to elucidate tissue injury-induced molecular changes.

Currently available drugs of plant or animal origins may provide satisfactory reduction of pain associated with tissue injury. Therefore, we are assessing the effects on pain and molecular changes induced by some of those agents, for example components of extracts prepared from the plant Cannabis sativa.

Among the tissue injury-induced molecular changes, alterations in gene expression in primary sensory neurons and cells of the spinal dorsal horn are pivotal for the long-term persistence of pain. Hypersensitivity to heat constitutes one of the main modalities of pain associated with tissue injuries and the subsequent inflammatory reaction. We have recently found that the nuclear enzyme mitogen- and stress-activated kinase 1 is indispensable for the development and long-term persistence of pain following tissue injury and inflammation. This enzyme has already been shown to control adaptive changes via regulating gene expression by inducing alterations in epigenetic tags and activating various transcription factors. Hence, we are using this enzyme as a guide to find the genes whose altered expression underlies the development and persistence of pain in tissue injury and subsequent inflammation.

Our main current activities are aimed:

• To identify molecular networks associated with tissue injuries in the injured tissue, primary sensory neurons and the spinal dorsal horn, including “checkpoint” molecules of those networks, which are involved in the development and persistence of pain associated with tissue injuries, for example with burn injury;
• To elucidate the contribution of the mitogen- and stress-activated kinase 1 for the development and persistence of hypersensitivity to heat following tissue injury and inflammation. 
• To assess the effect of some agents of plant or animal origins on tissue injury-induced molecular changes in peripheral tissues, primary sensory neurons and the spinal dorsal horn and on the development and persistence of pain associated with tissue injuries and subsequent inflammatory reactions.