Antinociceptive effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone in the land snail, Cepaea nemoralis.

Results of investigations with vertebrates have implicated neuroactive steroids and in particular 5alpha-reduced metabolites of progesterone such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/3A5P and originally allopregnanolone) in the rapid modulation of diverse functions including that of nociceptive sensitivity. These effects have been indicated to involve modulation of GABA receptors. Results of recent phylogenetic studies have revealed the presence of GABA receptors in invertebrates that may also be subject to modulation by steroids and neuroactive steroids. The present study examined the effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one, as well as progesterone on aversive thermal (nociceptive) responses in a mollusc, the land snail, Cepaea nemoralis. 3alpha-Hydroxy-5alpha-pregnan-20-one had significant dose-related (0.01-1.0 microg) antinociceptive effects in Cepaea increasing the latency of response to a 40 degrees C surface, with maximum effects being evident 15-30 min after administration. These effects of 3alpha-hydroxy-5alpha-pregnan-20-one were stereospecific, with the stereoisomer 3beta-hydroxy-5alpha-pregnan-20-one (3B5P) failing to affect nociceptive responses. Progesterone also had significant dose-related (0.10-10 microg) antinociceptive effects that, however, were delayed in onset and relatively prolonged (60-120 min), suggestive of the formation of active metabolites. The presence of endogenous progesterone (12.36+/-0.17 ng/g tissue) was ascertained by a radioimmunoassay further supporting a functional role for steroids in Cepaea. The antinociceptive effects of 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone were blocked by the GABA antagonists, bicuculline and picrotoxin, while being relatively insensitive to opioid and N-methyl-D-aspartate antagonists. These results suggest an early evolutionary development and phylogenetic continuity of neuroactive steroid and GABA involvement in the mediation of nociception.