Transplants of adrenal medullary chromaffin cells reduce forelimb and hindlimb allodynia in a rodent model of chronic central pain after spinal cord hemisection injury.

In the majority of patients, spinal cord injury (SCI) results in abnormal pain syndromes in which non-noxious stimuli become noxious (allodynia). To reduce allodynia, it would be desirable to implant a permanent biological pump such as adrenal medullary chromaffin cells (AM), which secrete catecholamines and opioid peptides, both antinociceptive substances, near the spinal cord. We tested this approach using a recently developed a mammalian SCI model of chronic central pain, which results in development of mechanical and thermal allodynia. Thirty day-old male Sprague-Dawley rats were spinally hemisected at T13 and allowed 4 weeks for recovery of locomotor function and development of allodynia. Nonimmunosuppressed injured animals received either control-striated muscle (n = 7) or AM (n = 10) transplants. Nociceptive behavior was tested for 4 weeks posttransplant as measured by paw withdrawals to von Frey filaments, radiant heat, and pin prick stimuli. Hemisected animals receiving AM demonstrated statistically significant reductions in both fore- and hindlimb mechanical and thermal allodynia, but not analgesia, when compared to hemisected animals receiving striated muscle transplants (P < 0.05). Tyrosine hydroxylase immunoreactivity indicated prolonged transplant survival and production of catecholamines. HPLC analysis of cerebrospinal fluid samples from animals receiving AM transplants demonstrated statistically significant increases in levels of dopamine (sevenfold), norepinephrine (twofold), and epinephrine (threefold), compared to control values several weeks following transplant (P < 0.05). By 28 days posttransplant, however, antinociceptive effects were diminished. These results support the therapeutic potential of transplanted AM in reducing chronic central pain following spinal cord injury.

Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury.

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.

Transplant therapy: recovery of function after spinal cord injury.

Spinal cord injuries (SCI) result in devastating loss of function and altered sensation. Presently, victims of SCI have few remedies for the loss of motor function and the altered sensation often experienced subsequent to the injury. A goal in SCI research is to improve function in both acute and chronic injuries. Among the most successful interventions is the utilization of transplanted tissues toward improved recovery. The theory is that the transplanted tissue could (1) bridge the spinal lesion and provide chemical and/or mechanical guidance for host neurons to grow across the lesion, (2) bridge the spinal lesion and provide additional cellular elements to repair the damaged circuitry, (3) provide factors that would rescue neurons that would otherwise die and/or modulate neural circuits to improve function. A variety of tissues and cells have been added to the adult mammalian spinal cord to encourage restoration of function. These include Schwann cells, motor neurons, dorsal root ganglia, adrenal tissue, hybridomas, peripheral nerves, and fetal spinal cord (FSC) tissue en bloc or as disassociated cells. It is postulated that these tissues would rescue or replace injured adult neurons, which would then integrate or promote the regeneration of the spinal cord circuitry and restore function. In some instances, host-appropriate circuitry is supplied by the transplant and functional improvement is demonstrated. In this presentation, specific examples of recent work with transplanted tissue and cells that demonstrate improved behavioral outcome are presented. New recent work describing the in vitro propagation and characterization of human fetal spinal cord multipotential progenitor cells are also described in the context of a potential resource for transplantable cells. Additionally, data from transplantation experiments of human FSC cells into nonimmunosuppressed rat spinal cord are described, and the resultant improvements in behavioral outcome reported. Lastly, directions for future SCI research are proposed.