enkephalin--ala(2)-mephe(4)-gly(5)- and capsazepine

Cannabinoids produce analgesia through a variety of mechanisms. It has been proposed that one mechanism is by modulating the release of CGRP in the spinal cord pain pathways. Previous studies have reported that cannabinoids, particularly CB2 receptor agonists, can modulate CGRP release in the isolated rat spinal cord. In our experiments, the TRPV1 agonist capsaicin evoked CGRP release and this was supressed by the TRPV1 antagonist capsazepine and by the opioid receptor agonist DAMGO. However, none of the cannabinoid receptor agonists that we tested were able to modulate evoked CGRP release; including WIN 55,212-2, methanandamide, and GW405833. These results question the role of spinal cord cannabinoid receptors in the regulation of CGRP signaling.

Topics: Animals; Arachidonic Acids; Benzoxazines; Calcitonin Gene-Related Peptide; Cannabinoid Receptor Agonists; Cannabinoids; Capsaicin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; In Vitro Techniques; Indoles; Lumbosacral Region; Male; Morpholines; Naphthalenes; Rats, Wistar; Receptors, Opioid; Sciatic Nerve; Spinal Cord; TRPV Cation Channels

Extracellular acidosis is a common feature in pain-generating pathological conditions. Acid-sensing ion channels (ASICs), pH sensors, are distributed in peripheral sensory neurons and participate in nociception. Morphine exerts potent analgesic effects through the activation of opioid receptors for various pain conditions. A cross-talk between ASICs and opioid receptors in peripheral sensory neurons has not been shown so far. Here, we have found that morphine inhibits the activity of native ASICs in rat dorsal root ganglion (DRG) neurons. Morphine dose-dependently inhibited proton-gated currents mediated by ASICs in the presence of the TRPV1 inhibitor capsazepine. Morphine shifted the proton concentration-response curve downwards, with a decrease of 51.4±3.8% in the maximum current response but with no significant change in the pH0.5 value. Another μ-opioid receptor agonist DAMGO induced a similar decrease in ASIC currents compared with morphine. The morphine inhibition of ASIC currents was blocked by naloxone, a specific opioid receptor antagonist. Pretreatment of forskolin, an adenylyl cyclase activator, or the addition of cAMP reversed the inhibitory effect of morphine. Moreover, morphine altered acid-evoked excitability of rat DRG neurons and decreased the number of action potentials induced by acid stimuli. Finally, peripheral applied morphine relieved pain evoked by intraplantar of acetic acid in rats. Our results indicate that morphine can inhibit the activity of ASICs via μ-opioid receptor and cAMP dependent signal pathway. These observations demonstrate a cross-talk between ASICs and opioid receptors in peripheral sensory neurons, which was a novel analgesic mechanism of morphine.

Topics: Acetic Acid; Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; Action Potentials; Analgesics, Opioid; Animals; Capsaicin; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Ganglia, Spinal; In Vitro Techniques; Male; Morphine; Naloxone; Narcotic Antagonists; Neurons; Nociception; Pain; Protons; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; TRPV Cation Channels