Focally administered nerve growth factor suppresses molecular regenerativeresponses of axotomized peripheral afferents in rats

Effects of delivery of nerve growth factor, from a catheterized osmotic min i-pump to the proximal stump of a transected sciatic nerve, were compared w ith the effects of normal saline. A pilot measured retrograde axonal transp ort of nerve growth factor to determine a pump concentration which raised a xonal transport ipsilaterally, but not contralaterally. The effects of this delivery over 12 days were then determined on expression of growth-associa ted protein-43, trkA, p75(NTR) and preprotachykinin A ipsilateral and contr alateral to the pump in dorsal root ganglia at L-4 and L-5 (pooled). Gangli onic expression was measured both as messenger RNA and protein. Axotomy (sa line pumps) increased growth-associated protein-43 messenger RNA (318 +/- 1 4%. all changes are percent of contralateral, non-axotomized ganglia with s aline pumps) and immunoreactivity (431 +/- 43%). The increase was significa ntly less (P < 0.001) ipsilateral to nerve growth factor pumps (191 +/- 45% ). Axotomy reduced expression of p75(NTR) (messenger RNA: 52 +/- 17%, P < 0 .01: immunoreactivity: 74 +/- 3%, P < 0.05). These decreases were converted to increases by nerve growth factor delivery (respectively 143 +/- 40% and 281 +/- 67%; both P < 0.01). With trkA, axotomy decreased the expression o f the messenger RNA (68 +/- 40%, P < 0.01) and of the primary translation p roduct-110,000 mol. wt protein (55 +/- 12%, P < 0.01)-but not the fully gly cosylated trkA protein (mol, wt 145,000). Nerve growth factor delivery did not affect trkA expression. Axotomy reduced messenger RNA for the substance P precursor, preprotachykinin A, to 42 +/- 17% (P < 0.01) and this reducti on was prevented by nerve growth factor treatment. We suggest that the primary effect of nerve growth factor on axotomized C-f ibres is not to promote regeneration, although that may be its secondary ef fect via an action on Schwann cells. It is possible that reduced neuronal s ensitivity to nerve growth factor during regeneration is advantageous in su ppressing nociception. (C) 1999 IBRO. Published by Elsevier Science Ltd.