Regulation of sigma activity by the amino-terminus of substance P in the mouse spinal cord: Involvement of phencyclidine (PCP) sites not linked to N-methyl-d-aspartate (NMDA) activity

Alice A Larson, Xiaofeng Sun

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14 Scopus citations

Abstract

Behavioral responses to kainic acid (KA) injected intrathecally in mice are enhanced by N- but not C-terminal fragments of substance P (SP). Repeated injections of KA result in sensitization to KA-induced activity, an effect that appears to be mediated by SP N-terminal activity and inhibited by PCP ligands. The present study was initiated to determine whether the ability of SP N-terminal fragments to enhance KA activity is also sensitive to PCP ligands. We compared the effect of a PCP ligand, dizocilpine (MK-801), to that of haloperidol, a sigma ligand and dopamine antagonist. MK-801 (1 nmol) failed to alter the enhancement of behavioral responses to KA (25 pmol) produced by SP(1-7) (22.5 pmol, 30 min). However, pretreatment with 1 nmol of either haloperidol or the N-terminal SP antagonist, [d-Pro2-d-Phe7]SP(1-7) [d-SP(1-7)], prevented potentiation of KA by SP(1-7). Like SP(1-7), 5 nmol of the sigma ligand 1,3-di(2-tolyl)guanidine (DTG) also enhanced behaviors elicited by KA, and this effect was also blocked by haloperidol or d-SP(1-7), but not spiperone (2.5 nmol), a dopamine antagonist. Together these data suggest that sigma receptors are involved in the potentiation of KA. A large dose of SP(1-7) (10 nmol) or DTG (20 nmol) did not alter the response to KA 24 hr later, yet further potentiated responses to KA 30 min after SP(1-7) (22.5 pmol) or DTG (5 nmol), sugesting sensitization to the effects of these compounds. Administered 5 min prior to SP(1-7) (10 nmol, 24 hr), MK-801 and PCP each prevented sensitization of mice to subsequent exposure to SP(1-7) (22.5 pmol, 30 min), while haloperidol and (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive N-methyl-d-aspartate (NMDA)-antagonist, did not. Sensitization to DTG was similarly inhibited by pretreatment with MK-801. These results suggest that while a sigma receptor mediates the short-term facilitation of KA-induced activity by either SP(1-7) or DTG, inhibition of PCP sites prevents the upregulation of sigma activity elicited by these compounds. The inability of CPP to mimic the effects of MK-801 and PCP suggest that these PCP sites may not be linked to NMDA activity.

Original languageEnglish (US)
Pages (from-to)909-917
Number of pages9
JournalNeuropharmacology
Volume32
Issue number9
DOIs
StatePublished - Sep 1993

Keywords

  • MK-801
  • N-terminus of SP
  • PCP
  • excitatory amino acids
  • haloperidol
  • kainic acid
  • sigma
  • substance P

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