P2X2/3 receptors, localized on peripheral and central terminals of primary sensory neurons, are involved in persistent nociceptive signalling. Opioid peptides are known to produce analgesia through central as well as via peripheral mechanisms. We have shown that in rat nodose neurons P2X2/3-mediated responses were modulated by opioids in a biphasic manner: an initial short phase of potentiation (300–400 s) was followed by long-lasting inhibition of the response (for about 50% at the steady-state level). Addition of GTP-gamma-S, GDP to the intracellular solution and preincubation with pertussis toxin indicated that P2X2/3 receptors were affected by opioids via Gprotein dependent pathways. We have also shown that sensitivity of P2X2/3 receptors to endomorphin-1 is altered after co-culturing of nodose neurons with fi brosarcoma cells (NCTC 2472). In co-cultured neurons ATP-activated currents with “slower” desensitization kinetics were less inhibited by the opioid. “Ultra-slow” responses were completely insensitive to endomorphin-1. The occurrence of these responses increased with the duration of co-culturing. Thus, coculturing decreases sensitivity of ATP responses to endomorphin-1, which can account for low sensitivity of cancer pain to opioids.
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