Lipid mediators regulating pain sensitivity

The papers in this symposium demonstrate that lipid molecules are ubiquitous messengers that participate in intracellular signaling, function in intercellular communication, and serve as neurotransmitters. This review examines the contribution of lipid messengers in regulating a specific physiological function, the transmission of noxious sensory information (pain) in the nervous system. Lipid molecules play major roles in the modulation of pain sensitivity. Six types of lipid molecules (prostanoids, phosphatidyl inositol bisphosphate, ceramide, lipoxygenase metabolites of arachidonic acid, fatty acyl dopamines, and acylethanolamides) have been shown to modulate systems important in the regulation of pain responses. These molecules exert their actions by interacting with varied receptor systems. Evidence for their participation in the regulation of pain responses comes from in vitro demonstrations of their interactions with signaling systems known to be important in the regulation of pain sensitivity and, in some cases, from demonstration of their ability to modulate pain sensitivity after in vivo administration. One of these classes of lipid mediators, the acylethanolamides, inhibits pain responses, while the others appear to enhance pain sensitivity. Given the rapid growth in our understanding of lipidomics, evident in the papers of this issue, it is virtually certain that additional lipid mediators will be identified as being central to the regulation of pain responses.     

Peptide fragments derived from the beta-chain of hemoglobin (hemorphins) are centrally active in vivo

A novel tetrapeptide (hemorphin-4) and pentapeptide (hemorphin-5), derived from the beta-chain of hemoglobin, were synthesized by solid-phase methodology, purified and the amino acid sequences confirmed. The central (ICV) effects of hemorphin-4 and -5 were studied in two models of phasic and tonic nociception, the mouse warm water tail-flick assay and hindpaw formalin assay, respectively. Additionally, two physiological endpoints, central modulation of bladder motility and central effects on intestinal propulsion, were studied in rats and mice, respectively. In the tail-flick assay, both peptides (40-100 nmoles) produced a dose-related naloxone-reversible antinociceptive effect when tested 10 min after peptide administration, with the tetrapeptide being slightly more potent than the pentapeptide. No effect was noted for either peptide using the tonic nociception assay, except at a dose of 150 nmoles for hemorphin-5. Inhibition of gastrointestinal propulsion was also not affected by either peptide. However, both peptides (10-40 nmoles) inhibited micturition contractions in a dose-related and naloxone-reversible fashion, with the tetrapeptide being twice as potent as the pentapeptide. These findings provide evidence that hemorphin-4 and -5 exert naloxone-reversible opioid actions in vivo and, therefore, may be physiologically important blood-borne peptides.