Metabotropic neurosteroid/sigma-receptor involved in stimulation of nociceptor endings of mice

In peripheral nociceptive flexor test, SA4503, (+)-pentazocine, and (+)-3-( hydroxyphenyl)-N-(1-propyl)piperidine, representative sigma-receptor agonis ts, elicited dose-dependent flexor responses. These responses were blocked by sigma-receptor antagonists NE-100 or BD1063, but not by pretreatments wi th antisense oligodeoxynucleotide for sigma1 binding protein. The sigma-ago nists' nociception is attributed to the substance P (SP) release from nocic eptor endings through activations of G alpha (i1) and phospholipase C (PLC) . On the other hand, attomolar doses of neurosteroids such as dehydroepiand rosterone sulfate (DHEAS) and pregnenolone sulfate caused similar nocicepti on, and they were blocked by progesterone (PROG). However, DHEAS nociceptio n was not affected by pertussis toxin, but was completely inhibited by a PL C inhibitor or thapsigargin. Although the nociception by lower doses of DHE AS was abolished by diphenhydramine (DPH), H1 antagonist, there were dose-d ependent responses by high doses of DHEAS in the presence of DPH. The respo nses by DHEAS in the presence of DPH were blocked by NE-100, and those by ( +)-pentazocine were blocked by PROG. All these findings suggest that two no vel types of neurosteroid receptors exist, neuronal NS1/sigma-type, which m ediates activation of G alpha (i1) by neurosteroids and sigma -agonists, fo llowed by SP release from nociceptor endings; and NS2 type, which mediates histamine release from mast cells by very low doses of neurosteroids.