Elimination of rat spinal substance P receptor bearing neurons dissociates cardiovascular and nocifensive responses to nicotinic agonists.Neuropharmacology. 2008 Feb; 54(2):269-79.N
Intrathecal (IT) delivery of nicotinic agonists evokes dose dependent nocifensive behavior and cardiovascular responses. Previous studies suggested that these effects may be attenuated by the loss of substance P positive (sP(+)) primary afferents. To further characterize these cell systems, we examined the effect of selectively destroying neurokinin 1 receptor bearing (NK1-r(+)) dorsal horn neurons on IT nicotinic agonist evoked responses. In the dorsal spinal cord, confocal immunohistochemical microscopy revealed that nAChR subunits (alpha3, alpha4, alpha5, beta2 and beta4), NeuN B (neuronal marker) and NK1-r were all co-expressed in the superficial dorsal horn; however alpha3, alpha5, beta2 and beta4 exhibited the highest degree of colocalization with NK1-r expressing neurons. After intrathecal substance P-saporin (sP-SAP), NK1-r(+) cell bodies and dendrites in the superficial dorsal horn were largely abolished. The greatest loss in co-expression of nAChR subunits with NK1-r was observed with alpha3, alpha5, beta2 and beta4 subunits. Following intrathecal sP-SAP, the nocifensive responses to all nicotinic agonists were reduced; however, in contrast, while cardiovascular responses evoked by IT nicotine were unaltered, IT cytisine and epibatidine exhibited enhanced tachycardia and pressor responses. These results indicate subunit-specific relationships between the NK1-r and nicotinic receptor systems. The loss of nocifensive activity after destruction of the NK1-r bearing cells in spite of the persistence of nicotinic subunits on other cells, emphasizes the importance of the superficial marginal neuron in mediating these nicotinic effects. Further, the exaggerated cardiovascular responses to cytisine following loss of NK1-r bearing cells suggest the presence of a nicotinic receptor-mediated stimulation of inhibitory circuits at the spinal level.