Evidence that the NH 2-terminus of substance P modulates N-methyl- d-aspartate-induced activity by an action involving σ receptors

Abstract

Behaviors induced in mice by intrathecal injections of either N-methyl- d-aspartate (NMDA) or kainic acid are modulated by NH 2-terminal fragments of substance P, such as substance P-(1–7). The action of substance P-(1–7) on kainic acid depends on σ receptor activity. The present study was designed to test the hypothesis that σ receptor activity is also necessary for modulation of NMDA by substance P-(1–7). Intrathecal injection of mice with NMDA results in a brief burst of biting and scratching behaviors which decrease in intensity when NMDA is injected repeatedly at 2 min intervals. Pretreatment with 1,3-di- O-tolylguanidine (DTG), a ligand at both σ 1 and σ 2 sites, converted NMDA-induced desensitization to sensitization, thereby enhancing tonic NMDA receptor activity. Although haloperidol (30 min) alone was without effect, the potentiation of NMDA-induced activity by DTG was abolished by haloperidol but unaffected by an equimolar dose of either spiperone or thiothixine, two dopamine receptor antagonists. When mice received substance P-(1–7), NMDA-induced behaviors were initially inhibited but then potentiated. Pretreatment with haloperidol prevented both inhibitory and potentiative effects of substance P-(1–7) whereas thiothixine did not, suggesting inhibitory as well as potentiative modulation of NMDA by σ receptor activity. Endogenous σ 1 receptor activity may enhance NMDA receptor activity as a treatment regimen that down-regulates σ 1 binding also inhibited responses to NMDA. In contrast, pretreatment with haloperidol just 5 min prior to challenge, which blocks both σ 1 and σ 2 receptor activity, increased responses to NMDA suggesting an inhibitory effect of σ 2 receptor activity. In summary, modulation of NMDA by substance P-(1–7) appears to depend on activity at σ sites as substance P-(1–7) mimicked the potentiative effects of DTG, while haloperidol inhibited the effects of both DTG and substance P-(1–7).