Alternative drugs to spinally administered opiates in animal models of neuropathic pain

Many progress in the understanding and the management of pain has been made since Melzach and Wall (1965) published the “Gate Control Theory”, 35 years ago. This theory emphasized that sensory input is subject to modulation at multiple levels in the central nervous system (CNS) and the modulation can be either excitatory or inhibitory. The dorsal horn of the spinal cord represents the first “gate” and is one of the levels on which research has focused to produce spinal analgesic drugs. The discovery of action of spinal level by Besson et al, 1973 was the first step, and that of spinal opiate receptors (Yaksh and Rudy, 1976) has opened the way to discovering multiple other receptors (adrenergic, cholinergic, purinergic …) as potential targets for pain modulatory substances (Coggeshall and Carlton, 1997). By the same way, our thinking about pain perception and maintenance – like in chronic pain states – has been in constant evolution and became even more complex.
The concept that sex differences may exist both in pain perception and is response to analgesics, not only related to a pharmacokinetic difference, is also slowly emerging. Recent articles in the medical literature highlight the importance to include female subjects in experimental drug research (in animal modes, in clinical practice for volunteers and patients studies) and to analyze their data separately (Berkeley KJ, 1997; Riley et al, 1999).
Today, most of us agree that persistence if chronic pain, in contrast to acute pain which is a normal response to tissue damage, offers no biological advantage and therefore, cause unnecessary suffering and distress. Evenmore, clinical and fundamental studies have stressed the important fact that chronic pain differs from acute pain and involves pathological mechanisms development at both peripheral and central levels of the nervous system. Among the common chronic pain syndromes, neuropathic pain remains one the more complex, frequently mistreated or undertreated (Ashburn and Staats, 1998).
Indeed, we are currently confronted to problems in pain relief: on one hand, for acute pain (postoperative, burns, intensive care …) we have potent and effective drugs such as opioids or local anesthetics, which are nonetheless not devoid of harmful side effects; on the other hand, in chronic pain management (of malignant or non malignant origin), we are still facing patients suffering from intractable pain, especially in neuropathic pain conditions, poorly responsive to the conventional analgesic drugs we can offer.
Our work will focus on the later problem. Using an animal model of neuropathic pain, we will explore which drugs could be proposed as spinal analgesics as alternative to opioids.