Cutting-Edge Search for Safer Opioid Pain Relief: Retrospective Review of Salvinorin A and Its Analogs

Abstract

Over the years, pain has contributed to low life quality, poor health, and economic loss. Opioids are very effective analgesic drugs for treating mild, moderate, or severe pain. Therapeutic application of opioids has been limited by short and long-term side effects. These side effects and opioid-overuse crisis has intensified interest in the search for new molecular targets and drugs. The present review focuses on salvinorin A and its analogs with the aim of exploring their structural and pharmacological profiles as clues for the development of safer analgesics. Ethnopharmacological reports and growing preclinical data have demonstrated the antinociceptive effect of salvinorin A and some of its analogs. The pharmacology of analogs modified at C-2 dominates the literature when compared to the ones from other positions. The distinctive binding affinity of these analogs seems to correlate with their chemical structure and in vivo antinociceptive effects. The high susceptibility of salvinorin A to chemical modification makes it an important pharmacological tool for cellular probing and developing analogs with promising analgesic effects. Additional research is still needed to draw reliable conclusions on the therapeutic potential of salvinorin A and its analogs.

Keywords: analgesic; analogs; opioid receptors; salvinorin A; side effects.

Figure 1

Neural circuits of pain and opioid site of action. Cortex and spinal cord communication modulate pain perception and offer targets for opioid drugs. Neural projections from peripheral tissue transmit nociceptive inputs through primary afferent fibers (1) to the spinal dorsal horn (SDH) before reaching the thalamus (2). Neural projections from thalamus target cortical sites (centers of pain processing, cognition, perceptions and integration) and amygdala (“emotional site”). The amygdala receives nociceptive inputs from the thalamus and cortex. The descending pain control system is mediated through projections from structures such as amygdala and hypothalamus to the periaqueductal gray matter (PAG) which in turn communicates with the rostral ventromedial medulla (RVM). The neural components within RVM [the nucleus raphe magnus (NRM) and nucleus reticularis paragigantocellularis (NRPG)] project to the spinal or medullary dorsal horns to directly or indirectly enhance or attenuate nociceptive transmission. The 5-hydroxytryptamine (5-HT) and enkephalin-containing neurons in the NRM project to the substantia gelatinosa of the dorsal horn and exert an inhibitory influence on transmission. Opioids sites of action include dorsal horn and peripheral terminals of nociceptive afferent neurons where opioids inhibit transmission. Opioids stimulate PAG and NRPG (blue asterisk), which in turn project to the rostroventral medulla. The locus coeruleus (LC) which receives inputs from the PAG releases noradrenalin to the dorsal horn, which in turn inhibits nociceptive transmission. Areas labeled 2–4 in red color and 5–8 in green color represent ascending and descending tracts, respectively.

Figure 2

Hypothetical representation of signal transduction and trafficking of mu [μ] and kappa [κ] opioid receptor. Converging downstream pathways are activated by salvinorin A and its analogs with selective action and varying affinity on their respective opioid receptor subtypes. Arrows, activation; T lines, blockade of function; βγ, G protein β-γ subunit; cAMP, cyclic adenosine monophosphate; ERK, extracellular signal-regulated kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinases; GRK-3, G protein-receptor kinase 3; P, phosphorylation; C → , cyclization of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP) through the cleavage of pyrophosphate.

Figure 3

The structures of salvinorin A (A) and its analogs (B–I).