Attenuation of NMDA-induced spinal hypersensitivity by adrenal medullary transplants.

Abnormal sensory hyperexcitability consequent to peripheral injury most likely involves activation of N-methyl-D-aspartate (NMDA) receptors in the spinal cord. This activation may lead to a cascade of neuroplastic events resulting in the exaggeration of sensory responses and the persistence of pathological pain states. Recent studies in our laboratory have demonstrated that the transplantation of adrenal medullary cells into the spinal subarachnoid space can alleviate pathological pain symptoms, possibly by reducing spinal hyperexcitability. The purpose of this study was to assess spinal NMDA activation-induced hypersensitivity to noxious and innocuous stimuli, and determine whether adrenal medullary transplants can intervene favorably to reduce these responses. Animals with either adrenal medullary or control transplants were injected intrathecally with several doses of NMDA, and responses to sensory stimuli were determined over time. NMDA at all doses tested (1-50 nmol) produced significant thermal and mechanical hyperalgesia and tactile allodynia in control transplanted animals, with peak severity at 30 min post-injection. In contrast, both the severity and duration of these exaggerated sensory responses were markedly reduced in animals with adrenal medullary transplants. To assess a possible contribution of released opioid peptides and catecholamines from the transplanted chromaffin cells, animals were pretreated with opiate antagonist naloxone or alpha-adrenergic antagonist phentolamine. While naloxone was ineffective, the phentolamine partially attenuated, but did not completely abolish, the antinociceptive effects of the transplants. The results of these studies demonstrate that adrenal medullary grafts can reduce hypersensitivity responses to NMDA-mediated activation via alpha-adrenergic modulation in addition to other neuroprotective mechanisms.