Integrative pain research

Group members

Jingxia Hao – Senior researcher

Zsuzsanna Wiesenfeld-Hallin – Professor emerita

Xiaojun Xu – Senior lecturer, research group leader

Projects

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.

References

1. Bennett GJ. In: Wall PD, Melzack R (Eds):1994 Textbook of Pain. Churchill Livingstone, Edinburgh: pp 201-224
2. Boivie J. In: Wall PD, Melzack R (Eds): 1994 Textbook of Pain. Churchill Livingstone, Edinburgh: pp 871-902
3. Xu X-J et al. 1992 Pain 48 279-290
4. Kupers R et al. 1998 Pain 76 45-59
5. Eriksson J et al. 2005 Pain 119 82-94
6. Hökfelt T et al.1993 Trends Neurosci 17 22-30
7. Hao J-X et al. 1991 Pain 45 175-185
8. Gazelius B et al. 1996 NeuroReport, 7 2619-2623
9. Hao J-X et al 2000 Exp. Neurol 163 231-238
10. Yu W et al. 2000 J Peripheral Nervous System 5 209-217
11. Hao J-X et al. 2004 J Neurophysiol 92 1391-1399
12. Colpaert FC et al. 2002 Neuropharmacol 43 945-958
13. Hao J-X et al. 2006 Europ J Pharmacol 553 135-140
14. Endo T et al. 2008 Pain 138 292-300
15. Dominguez CA et al. 2009 Gender Medicine 6 225-234
16. Xu X-J et al. 1994 Pain 56 271-278
17. Xu X-J et al. 2003 Trends Pharmacol Sci 24 634-639
18. Watkins LR et al. 2001 Pain 93 201-206
19. Hao J-X et al. 1992 Exp Neurol 118 143-152
20. Marchand F et al. 2008 Europ J Pain Epub
21. Hao J-X et al. 2000 Neurosci Lett 280 211-214
22. Wiesenfeld-Hallin Z. 2002 Drugs 55 1-4
23. Hao J-X, Xu X-J. 1996, Pain, 66, 279-286
24. Xu X-J, Wiesenfeld-Hallin Z. In: JS Mogil (Ed) The Genetics of Pain, IASP Press, Seattle pp 107-121
25. Dominguez CA et al. 2008 Pain 136 313-319
26. Dominguez CA et al. 2008 Neurosci Lett 443 95-98
27. Paulson PE et al. 1998 Pain 76 223-229
28. Mogil JS et al. 1993 Pain 53 17-25
29. Dao TT, LeResche L. 2000 J Orofacial Pain 14 169-184
30. Aloisi AM, Ceccarelli I. 2000 Neuroscience 95 559-566
31. Xu X-J et al. 1997 Cytokine 9 1028-1033
32. Li LL et al. 2009 Pain 143 37-40

Publications

Sex differences in the development of localized and spread mechanical hypersensitivity in rats after injury to the infraorbital or sciatic nerves to create a model for neuropathic pain.
Dominguez CA, Kouya PF, Wu WP, Hao JX, Xu XJ, Wiesenfeld-Hallin Z
Gend Med 2009 ;6 Suppl 2():225-34

Ablation of estrogen receptor alpha or beta eliminates sex differences in mechanical pain threshold in normal and inflamed mice.
Li L, Fan X, Warner M, Xu XJ, Gustafsson JA, Wiesenfeld-Hallin Z
Pain 2009 May;143(1-2):37-40

Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury.
Endo T, Spenger C, Hao J, Tominaga T, Wiesenfeld-Hallin Z, Olson L, et al
Pain 2008 Aug;138(2):292-300

Genetic analysis of neuropathic pain-like behavior following peripheral nerve injury suggests a role of the major histocompatibility complex in development of allodynia.
Dominguez CA, Lidman O, Hao JX, Diez M, Tuncel J, Olsson T, et al
Pain 2008 Jun;136(3):313-9

Sex differences in pain perception.
Wiesenfeld-Hallin Z
Gend Med 2005 Sep;2(3):137-45

Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome.
Hofstetter CP, Holmström NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, et al
Nat. Neurosci. 2005 Mar;8(3):346-53

A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury.
Wu WP, Hao JX, Ongini E, Impagnatiello F, Presotto C, Wiesenfeld-Hallin Z, et al
Br. J. Pharmacol. 2004 Jan;141(1):65-74

Opioid hyperalgesia and tolerance versus 5-HT1A receptor-mediated inverse tolerance.
Xu XJ, Colpaert F, Wiesenfeld-Hallin Z
Trends Pharmacol. Sci. 2003 Dec;24(12):634-9

Physiological and pharmacological characterization of a rat model of spinal cord injury pain after ischemic spinal cord injury.
Xu XJ, Hao JX, Wiesenfeld-Hallin Z.
In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 17587.

Contact us