REGULATION OF THE 2ND-MESSENGER SYSTEMS IN THE RAT SPINAL-CORD DURINGPROLONGED PERIPHERAL INFLAMMATION

Unilateral intraplantar injection of Freund's complete adjuvant (FCA) into 1 hind paw of rats was used as a model of peripheral inflammation and persistent pain in order to examine time course effects of a cont inuous barrage of nociceptive input on the second-messenger transducin g systems in the spinal cord. cAMP, cGMP and inositol 1,4,5-trisphosph ate (insP(3)) were extracted from the lumbosacral cord at days 1, 7, 1 4, 21 and 42 following FCA injection and quantified by either radiorec eptorassay (RRA) or radioimmunoassay (RIA). The lumbosacral contents o f cAMP and cGMP when quantified in whole lumbosacral cord segment were not significantly changed by FCA treatment at all time points. InsP(3 ) accumulation was significantly increased on days 14, 21 and 42 follo wing FCA injection relative to sham-treated time-matched controls. How ever, cGMP and insP(3) contents were significantly increased in the le ft longitudinal half of the lumbar enlargement ipsilateral to the inje cted paw on day 21 following FCA treatment, but not in the sham-treate d time-matched controls. With [H-3]insP(3) as a ligand, Scatchard (Ros enthal) analyses of the concentration-dependent saturation curves show ed that the densities (B-max) of insP(3) receptors (insP(3)R) were sig nificantly increased throughout the time course of adjuvant-induced pe ripheral inflammation. The binding affinities (K-D) for insP(3)R were significantly decreased on days 7, 14 and 21 following FCA injection c orresponding to the times of most stable and peak inflammation. InsP(3 )R from the cerebelli of the same rats as used in the lumbosacral insP (3)R characterization was used as a positive control in this study and did not show any change in both B-max and K-D as a result of FCA trea tment, thus demonstrating that the changes in lumbosacral insP(3)R cha racteristics might be specific to the nociceptive sensory pathway such as the spinal cord. Thus it appears that sustained afferent nocicepti ve input induced by FCA injection increased the accumulation of cGMP, insP(3) and insP(3)R density in the spinal cord through increased neur onal activities of functional receptors coupled to major classes of ch emical mediators of nociception including neuropeptides and excitatory aminoacids. Changes in insP(3) accumulation in the lumbosacral cord f ollowing FCA injection were significantly correlated with changes in i nsP(3)R density. Changes in the ratios of lumbosacral insP(3) contents and insP(3)R density were also significantly correlated with changes in body weight and hind paw size induced by FCA injection. Thus, a rel ationship is established between modulation in the spinal cord insP(3) /insP(3)R system, an intracellular calcium-mobilizing transduction sys tem, and modifiable systemic variables induced by peripheral inflammat ion.