Abstract
Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.
Highlights
Sigma-1 receptors are expressed in important areas for pain control within the central and the peripheral nervous system
Acute nociceptive behaviors and secondary mechanical allodynia induced by the intraplantar administration of capsaicin to wild-type mice
We tested the ability of different doses of capsaicin to induce secondary mechanical allodynia
Summary
Sigma-1 receptors are expressed in important areas for pain control within the central and the peripheral nervous system. Some studies showed that the administration of selective σ1 agonists such as PRE-084 or (+)-pentazocine had the opposite effects to σ1 antagonists, i.e., σ1 agonism was able to induce or promote pain hypersensitivity[23,26,27,28,29,30,31]. To clarify whether σ1 activation is able to enhance pain sensitivity, we studied the effects of the acute administration of selective and nonselective σ1 agonists in different experimental pain conditions. We aimed to test whether chronic σ1 activation by the selective σ1 agonist PRE-084 is able to induce sensitization to mechanical stimuli per se or to promote mechanical hypersensitivity after the administration of capsaicin, and whether its effects are due to the altered expression of σ1 receptors in key areas of the pain pathways in the central and peripheral nervous system
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