Research Guy Hans

Abstract

Endothelin-1 is being increasingly recognized as an important molecule in the development and progression of cancer, but also in the occurrence of cancer pain. So far, all studies have used acute administration of ET-1, bearing little resemblance with the prolonged exposure observed in clinical conditions. It is therefore proposed to investigate the effects of chronic exposure to ET-1 on signs of spontaneous and evoked pain behaviour.

Researcher(s)

• Promoter: Deseure Kristof
• Co-promoter: Hans Guy

Research team(s)

• Antwerp Surgical Training, Anatomy and Research Centre (ASTARC)

Project type(s)

• Research Project

Abstract

In this project an innovative approach to the diagnosis of pain in ICU patients will be developed. On the basis of this objective measurement of pain, a mechnism-based treatment for individual patients will be studied.

Researcher(s)

• Promoter: Hans Guy

Research team(s)

• Translational Neurosciences (TNW)

Project website

Project type(s)

• Research Project

Abstract

Endothelin-1 is being increasingly recognized as an important molecule in the development and progression of cancer, but also in the occurrence of cancer pain. So far, all studies have used acute administration of ET-1, bearing little resemblance with the prolonged exposure observed in clinical conditions. It is therefore proposed to investigate the effects of chronic exposure to ET-1 on signs of spontaneous and evoked pain behaviour.

Researcher(s)

• Promoter: Deseure Kristof
• Co-promoter: Hans Guy
• Co-promoter: Vercauteren Marcel P E

Research team(s)

• Antwerp Surgical Training, Anatomy and Research Centre (ASTARC)
• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

For the first time we will try to extrapolate in this study the basic findings concerning the role of Endothelin-1 as a pain mediator towards humans. For this purpose the development and time progression of a cutaneous hyperalgesia will be examined in healthy volunteers. In order to perform these investigations we will be using state of the art neurophysiological research techniques, such as quantitative sensory testing.

Researcher(s)

• Promoter: Hans Guy

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

In this model, the potent vasoconstrictor Endothelin-1 (ET-1) will be administered to the infra-orbital nerve (IoN) of male Sprague-Dawley rats. The infra-orbital nerve of the rat is indeed extremely suited for the investigation of neuropathic pain syndromes because the IoN has a entirely sensoric function, without any motor function. This offers a great advantage compared to the often used sciatic nerve, which consists of a combination of motor and sensory components. Furthermore, clinical manifestation of a IoN injury induced pain syndrome can be fairly easy measured and investigated in a laboratory setting. Application of ET-1 will probably result in occurrence of spontaneous and evoked neuropathic pain symptoms in the facial area of the rats. After application of ET-1 to the IoN of the rat, animals will be tested for the presence of spontaneous pain (determination of spontaneous face-grooming behavior), as well as evoked pain sensations (after mechanical and thermal stimulation). Pain symptoms after innocuous mechanical stimulation (mechanical allodynia) will be induced by stimulating the facial area (zone I-II-III) with increasing sizes of von Frey hairs. For the investigation of the development of thermal allodynia we will use an entirely new method of investigation. Indeed, until now, thermal stimulation was almost never applied in laboratory settings due to the lack of standardization and reproducibility. In recent months we particpated in the development of system to apply short and well-defined thermal stimuli by remote control (in order to avoid the occurrence of sensitization on repeated stimulation in the animals). Hereby, we can apply a very precise repeatable stimulus to the animal. We can do this in two possible ways. Option 1: Apply a set amount of heat for a set amount of time. This can be set by the user and changed at any time. Option 2: Increasing controlled amount of heat. The user can set a starting temperature, a cutoff temperature and the ramp time. We can set a cutoff temperature to reduce the risk of tissue and nerve damage. Once the animal reacts the user can stop the stimulus and the temperature and time would be recorded automatically. In option 1 the one thing I would like to mention is that the heat source would need a very short amount of time to reach its set temperature, (something less than one second). The time of the stimulus can also be changed at anytime. The reaction of the animal will then be determined by the experimenter. The implementation of this method will mean that for the very first time rats can be objectively tested for the presence of thermal hyperalgesia and/or allodynia! Our lab will be the first lab in the world to be able to perform this sophisticated way of performing thermal testing in rats. The possibility of being able to investigate the presence and extent of thermal allodynia has to be considered as of extreme value since thermal allodynia is one of the most important characteristics of (common) clinical neuropathic pain syndromes. In addition, the infra-orbital nerve allows the use of several different methods of application of ET-1, which will provide us with extremely important ways of mimicking all kinds of both acute and chronic clinical conditions. More precisely, we will be able to perform extraneural application of ET-1 in acute (one single application of ET-1) and chronic conditions (implantation of osmotic pump in the surroundings of the IoN with continuous long-term application of very low doses of ET-1, mimicking the clinical 'ie. oncological- conditions). Also, intraneural application of ET-1 will be performed, as a model of intraneural invasion of tumor cells in clinical conditions. Finally, subcutaneous injection of ET-1 is possible in the facial area of the rat, which allows (electrophysiologic, morphological and biochemical) research into the pathophysiology of cutaneous hyperalgesia and allodynia (a condition seen in many oncological,

Researcher(s)

• Promoter: Hans Guy
• Co-promoter: Adriaensen Hugo

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Pain in patients with metastatic cancer contributes to increased suffering in those already burdened by their advancing illness. The causes of this pain are unknown, but likely to involve the action of tumor-associated mediators and their receptors. One such mediator, endothelin-1 (ET-1), can induce both pain-like behavior in animals and pain in humans that is endothelin-A (ETA) receptor-dependent, and that appears to be due to the selective excitation of pain fibers. More significantly, in clinical studies, antagonists of the ETA receptor have been shown to ameliorate pain in some patients with advanced metastatic prostate cancer. The identification of tumor-associated mediators such as ET-1 that might directly or indirectly cause pain in patients with metastatic disease should lead to improved, targeted analgesia for patients with advanced cancer. Although the mechanism of action for ET-1 induced pain in animals or humans has not been established, our recent studies suggest that this pain may be due to the direct excitation of sensory fibers. For example, we have observed that the application of ET-1 to rat sciatic nerve induces pain behavior, whereas identical application of equipotent vasoconstrictors, such as epinephrine, does not induce pain behavior. Furthermore, we have recently shown that subcutaneous injection of ET-1 into the plantar hindpaw of the rat both induces pain behavior and, quickly and selectively, excites C and could be due to the direct activation of nociceptive sensory afferents. It is necessary to distinguish between direct chemical excitation of nociceptors and their sensitisation to physical stimuli. Excitation and sensitisation may depend on different membrane processes. In a first step we will establish whether (acute) intradermal injection of ET-1 in humans causes acute, ongoing, spontaneous pain. Following the establishment of the pain threshold, we will establish whether intradermal administration of ET-1 in human subjects induces sensitization to subsequent non-noxious mechanical stimuli (touch evoked allodynia). Finally, we will establish the fiber-type that mediates the ET-1 induced sensitisation, using quantitative sensory testing techniques (thermal testing). Mechanical hyperalgesia and allodynia are mainly initiated by activation of myelinated nociceptive afferents. In contrast, thermal hyperalgesia is initiated mainly via activation of unmyelinated nociceptors.

Researcher(s)

• Promoter: Hans Guy

Research team(s)

Project type(s)

• Research Project