Integrative pain research
Research in our group aims at identifying the mechanisms underlying neuropathic pain and to find treatments for the condition.
Neuropathic pain - a type of chronic pain - as a result of injury or due to diseases of the nervous system is a significant medical and socio-economic problem because it is so complex, long-lasting and difficult to treat.
Our understanding of the mechanisms behind neuropathic pain is still limited. In addition, one must keep in mind that other types of pain, such pain caused by cancer or arthritis, may include components of neuropathic pain during the chronic stage of the diseases. Pain after injury to the central nervous system is a special form of neuropathic pain that is particularly difficult to treat.
We have established new models of neuropathic pain that enable us to study conditions such as carpal tunnel syndrome and trigeminal neuralgia. The goals of our research are to use these models to explore the mechanisms of neuropathic pain and to seek effective treatments.
Physicians know that patients with identical injuries vary considerably in how much pain they report. One theory is that genetic factors may have an important role in determining an individual's pain sensitivity. We are carrying out studies to identify genes that may underlie susceptibility to pain, particularly neuropathic pain.
It has been known for some time that there are gender differences in the prevalence of many painful conditions among humans. Women tend to be overrepresented in most chronic pain conditions, though not all. In our group we study sex differences in acute pain perception and the development of chronic neuropathic pain. We intend to develop and refine models of chronic pain for clinical conditions that are more prominent among women.
Neuropathic pain (NP) after injury or due to diseases of the nervous system is a clinical problem because of its complexity, chronicity and treatment resistance (1). The mechanisms underlying NP are poorly understood. Central pain after injury to the central nervous system is particularly difficult to treat (2).
We have developed a model of central pain after ischemic injury to the spinal cord of the rat. Many features of this model are similar to pain in patients with spinal cord injury (3). We use this technique to produce peripheral nerve ischemia and have developed neuropathic models that may have relevance to clinical conditions (4, 5). The overall goals of our research group are to use these models to explore the mechanisms of neuropathic pain and to seek effective treatments.
Models of neuropathic pain
The underlying pathophysiological mechanisms of neuropathic pain are complex and not well understood. One major obstacle to study such mechanisms is that our understanding of pain physiology and pharmacology was built primarily on studies of nociceptive pain. Neuropathic pain in many aspects differs from nociceptive pain (1, 6). Clinical research on neuropathic pain is difficult as homogenous patient samples for important variables are difficult to obtain. Furthermore, invasive methods have to be used to address the underlying mechanisms and novel unproven treatments tested.
All these problems speak for the need to produce validated models of human neuropathic pain conditions in laboratory animals. Our laboratory uses a photochemical technique to produce ischemic spinal cord injury to develop models of spinal cord injury pain (3, 7). We have applied the same technique to produce partial injury to peripheral nerve in rodents, including sciatic nerve injury in rats and mice (4, 8, 9) and infraorbital nerve injury in rats (5). These models have been extensively characterized morphologically, electrophysiologically, behaviorally and pharmacologically (3-5, 10, 11). They have been used in studies of pain mechanisms, sex differences in pain and in preclinical development of novel analgesics (11-15).
Role of opioids in pain after spinal cord injury
Clinically relevant models of neuropathic pain have allowed us to study its mechanisms. We have shown, for example, that dysfunction of the endogenous opioid system may play an important role in the development of chronic pain-like behaviors in rats after spinal cord injury. Thus, administration of the opioid receptor antagonist naloxone, as well as selective antagonists for the µ or º opioid receptors, triggers pain-like behaviors in SCI rats that did not develop pain (16). Furthermore, pain-like behaviors can be effectively treated by a receptor antagonist for the anti-opioid peptide cholecystokinin (16). This involvement of endogenous opioids in the development of SCI pain as shown by our behavioral studies has been confirmed by a recent fMRI study in these rats (14). Interestingly, administration of naloxone in the subpopulation not exhibiting pain induces pain and increases the brain activation to the level of those with ongoing pain, which supports our behavioral data (14).
Potential alteration in endogenous pain modulation in rats with injuries to the spinal cord may lead to chronic pain through reverse tolerance (12, 17). Thus, chronic administration of opioids during chronic pain leads to tolerance and hyperalgesia (17). Conversely, administration of pain-enhancing agents under chronic pain produces reverse tolerance and analgesia (17). In several chronic pain models, including our spinal cord injury model, a 5-HT A1 receptor agonist, produced pain acutely, but alleviated pain upon chronic infusion (12). The results have led to the clinical development of this compound, currently in phase 3a trials, to treat neuropathic pain, including that in patients with spinal cord injuries.
Role of glia in pain after spinal cord injury
Glial cells (microglia and astrocytes) in the spinal cord and brain may play a role in pain after peripheral nerve injury (18). After spinal cord injury, there is a markedly increased level of gliosis close to the lesion (19). Spinal cord neurons in this area exhibit hyperexcitability correlating with pain behavior (11). Hence, local gliosis, plasticity in supraspinal glia and increased release of pro-inflammatory cytokines may play a role in spinal cord injury pain. Systemic administration of minocycline, which blocks glial cell activation, reduces pain in rats with injuries to the spinal cord (20).
Genetics of neuropathic pain
The sensitivity among different individuals to painful stimulation and to analgesic treatment varies. Genetic factors may underlie the variability in the development of neuropathic pain (24). Identifying the gene or genes that are responsible for strain differences in the development of neuropathic pain is an important step in understanding its mechanisms. We conducted genetic studies on the role of the major histocompatibility complex (MHC) in neuropathic pain after peripheral nerve injury using the approach of congenic strains and back-crossing (25, 26). While the MHC does not appear to play a role in spinal cord injury pain, marked differences were observed between strains of rats (26). We plan to conduct a large-scale breeding experiment between these rats in order to conduct quantitative trait-loci experiments to specific genomic regions that are responsible for difference in pain occurrence after SCI. This may allow us to identify genes that are involved in SCI pain.
Gender and pain
Women are more sensitive to acute noxious stimuli than men (27) and a similar sex difference in nociception has been found in rodents (28). The prevalence of chronic pain is higher in women than men as well (27), but experimental studies in models of chronic neuropathic pain have been inconsistent; female animals have sometimes been shown to be more and sometimes less prone to the development of neuropathic pain (29). There is considerable literature on the effect of gonadal hormones on pain sensitivity, but again, the effect of these hormones in the development of chronic pain has not been addressed (30).
Our laboratory is one of the first in the world to study sex differences in experimental neuropathic pain in genetically modified mice (31) and in mice lacking estrogen alpha and beta receptors (32). We have carried out systematic studies on sex differences in the development of neuropathic pain in rats after injury to the sciatic and infraorbital nerves. Our studies found that female rats are more susceptible to the development of localized (i.e., within the dermatome of the injured nerve) and extra-territorial wide-spread (outside the dermatome) pain-like behaviors, particularly after facial nerve injury. These results (15) may be relevant to our understanding of pain syndromes that predominantly affect women.
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A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury.
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