Spinal
transplantation of adrenal medullary chromaffin cells has been shown to decrease
pain responses in several animal models. Improved potency may be possible by engineering cells to produce greater levels of naturally derived
analgesics. As an initial screen for potential candidates, adrenal medullary transplants were evaluated in combination with exogenously administered
neuropeptides in rodent
pain models.
Histogranin is a 15-amino
acid peptide that exhibits
NMDA receptor antagonist activity. The stable derivative [Ser1]
histogranin (SHG) can attenuate
pain symptoms in some animal models. The
formalin model for neurogenic inflammatory
pain and the chronic constriction injury (CCI) model for
neuropathic pain were used to evaluate the combined effects of chromaffin cell
transplantation and intrathecal (IT) SHG
injections. Animals were implanted with either adrenal medullary or control striated muscle tissue in the spinal subarachnoid space. For evaluation of
formalin responses, animals were pretreated with SHG (0.5, 1.0, 3.0 microg) followed by an intraplantar injection of
formalin, and flinching responses were quantified. Pretreatment with SHG had no significant effect on flinching behavior in control animals at lower doses, with incomplete attenuation only at the highest dose. In contrast, 0.5 microg SHG significantly reduced flinching responses in animals with adrenal medullary transplants, and 1.0 microg nearly completely eliminated flinching in these animals in the tonic phase. For evaluation of effects on
neuropathic pain, animals received transplants 1 week following CCI, and were tested for thermal and
mechanical hyperalgesia and cold
allodynia before and following SHG treatment. The addition of low doses of SHG nearly completely eliminated
neuropathic pain symptoms in adrenal medullary transplanted animals, while in control transplanted animals only
thermal hyperalgesia was attenuated, at the highest dose of SHG. These results suggest that SHG can augment adrenal medullary transplants, and the combination may result in improved effectiveness and range in the treatment of
chronic pain syndromes.