Prosaptide (TM) D5 reverses hyperalgesia: inhibition of calcium channels through a pertussis toxin-sensitive G-protein mechanism in the rat

A retro-inverso 11-mer peptidomimetic of prosaposin, Prosaptide(TM) D5, ind uced neurite outgrowth in NS20Y neuroblastoma cells and enhanced [S-35]GTP gamma S binding to rat synaptosomal membrane at low nanomolar concentration s similar to prosaposin. Intramuscular injection of D5 ameliorated thermal hyperalgesia in the Seltzer rat model of neuropathic pain, returning paw wi thdrawal latency to control levels within 3 h after treatment. The effect w as sustained for at least 48 h after injection. Prosaposin and D5 inhibited K+-stimulated synaptosomal Ca-45(2+) uptake similar to omega-conotoxin MVI IC, demonstrating that both effecters modulated voltage-dependent calcium c hannels (VDCC); inhibition was largely abolished by pretreatment with pertu ssis toxin before D5 treatment. The results suggest a mechanism whereby VDC C are modulated by a pertussis toxin-sensitive G-protein coupled receptor; D5 binds to this receptor and thereby ameliorates hyperalgesia in the Seltz er model of neuropathic pain. (C) 2000 Elsevier Science Ireland Ltd. All ri ghts reserved.