EVIDENCE THAT THE NH2-TERMINUS OF SUBSTANCE-P MODULATES N-METHYL-D-ASPARTATE-INDUCED ACTIVITY BY AN ACTION INVOLVING SIGMA-RECEPTORS

Behaviors induced in mice by intrathecal injections of either N-methyl -D-aspartate (NMDA) or kainic acid are modulated by NH2-terminal fragm ents of substance P, such as substance P-(1-7). The action of substanc e P-(1-7) on kainic acid depends on a receptor activity. The present s tudy was designed to test the hypothesis that sigma receptor activity is also necessary for modulation of NMDA by substance P-(1-7). Intrath ecal injection of mice with NMDA results in a brief burst of biting an d scratching behaviors which decrease in intensity when NMDA is inject ed repeatedly at 2 min intervals. Pretreatment with 1,3-di-O-tolylguan idine (DTG), a ligand at both sigma(1) and sigma(2) sites, converted N MDA-induced desensitization to sensitization, thereby enhancing tonic NMDA receptor activity. Although haloperidol (30 min) alone was withou t effect, the potentiation of NMDA-induced activity by DTG was abolish ed by haloperidol but unaffected by an equimolar dose of either spiper one or thiothixine, two dopamine receptor antagonists. When mice recei ved substance P-(1-7), NMDA-induced behaviors were initially inhibited but then potentiated. Pretreatment with haloperidol prevented both in hibitory and potentiative effects of substance P-(1-7) whereas thiothi xine did not, suggesting inhibitory as well as potentiative modulation of NMDA by sigma receptor activity. Endogenous sigma(1) receptor acti vity may enhance NMDA receptor activity as a treatment regimen that do wn-regulates sigma(1) binding also inhibited responses to NMDA. In con trast, pretreatment with haloperidol just 5 min prior to challenge, wh ich blocks both sigma(1) and sigma(2) receptor activity, increased res ponses to NMDA suggesting an inhibitory effect of sigma(2) receptor ac tivity. In summary, modulation of NMDA by substance P-(1-7) appears to depend on activity at sigma sites as substance P-(1-7) mimicked the p otentiative effects of DTG, while haloperidol inhibited the effects of both DTG and substance P-(1-7).