Antagonism by haloperidol and its metabolites of mechanical hypersensitivity induced by intraplantar capsaicin in mice: role of sigma-1 receptors

Abstract

Rationale We evaluated the effects of haloperidol and its metabolites on capsaicin-induced mechanical hypersensitivity (allodynia) and on nociceptive pain induced by punctate mechanical stimuli in mice. Results Subcutaneous administration of haloperidol or its metabolites I or II (reduced haloperidol) dose-dependently reversed capsaicin-induced (1μg, intraplantar) mechanical hypersensitivity of the hind paw (stimulated with a nonpainful, 0.5-g force, punctate stimulus). The order of potency of these drugs to induce antiallodynic effects was the order of their affinity for brain sigma-1 (σ 1 ) receptor ([ 3 H](+)-pentazocine-labeled). Antiallodynic activity of haloperidol and its metabolites was dose-dependently prevented by the selective σ 1 receptor agonist PRE-084, but not by naloxone. These results suggest the involvement of σ 1 receptors, but discard any role of the endogenous opioid system, on the antiallodynic effects. Dopamine receptor antagonism also appears unlikely to be involved in these effects, since the D 2 /D 3 receptor antagonist (−)-sulpiride, which had no affinity for σ 1 receptors, showed no antiallodynic effect. None of these drugs modified hind-paw withdrawal after a painful (4 g force) punctate mechanical stimulus in noncapsaicin-sensitized animals. As expected, the control drug gabapentin showed antiallodynic but not antinociceptive activity, whereas clonidine exhibited both activities and rofecoxib, used as negative control, showed neither. Conclusion These results show that haloperidol and its metabolites I and II produce antiallodynic but not antinociceptive effects against punctate mechanical stimuli and suggest that their antiallodynic effect may be due to blockade of σ 1 receptors but not to dopamine receptor antagonism.

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

“…These results suggest that sigma-1 antagonism requires the presence of immune cells harboring EOPs to induce their opioid-dependent effects but that this is not the only mechanism used by sigma-1 antagonists to ameliorate pain. Our results are consistent with previous findings that the ameliorative effects of nonselective sigma-1 antagonists (i.e., haloperidol and its metabolites) in behavioral models involving central sensitization (such as the second phase of formalin-induced pain or capsaicin-induced secondary mechanical hypersensitivity) are not reversed by naloxone (26,27). The sigma-1 receptor is a ligand-regulated chaperone that participates in pain neurotransmission through multiple pathways (3).…”

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

“…As expected, the known s 1 antagonist BD-1063 inhibited [ 3 H](1)-pentazocine specific binding in a concentration-dependent manner, with an IC 50 value of 40.21 6 3.24 nM. This value was similar to that found in previous studies (Entrena et al, 2009a;Cobos et al, 2005Cobos et al, , 2006Cobos et al, , 2007. However, none of the opioid drugs (fentanyl, oxycodone, morphine, buprenorphine, tramadol, loperamide, naloxone, or naloxone methiodide) significantly inhibited [ (Fig.…”

“…Most experiments were performed in female WT (Charles River, Barcelona, Spain) and s 1 -KO CD-1 mice (Laboratorios Esteve, Barcelona, Spain) weighing 25-30 g. The knockout mice were backcrossed for 10 generations to a CD-1 genetic background as described previously (Entrena et al, 2009a). Some experiments were also performed in male WT mice to ensure that sex differences did not affect our results.…”

“…The cold drugs tested were the following opioids: fentanyl, oxycodone, morphine, buprenorphine, loperamide, tramadol, naloxone, and naloxone methiodide. BD-1063 was used as a control with known high affinity for s 1 receptors (Cobos et al, 2007;Entrena et al, 2009a). All drugs were dissolved at a concentration of 1 mM in ultrapure water with the exception of loperamide, which was dissolved in absolute ethanol.…”

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

“…Moreover, recent studies using σ1R knock‐out mice and pharmacological interventions with selective σ1R antagonists (Romero et al., 2012) showed an antinociceptive effect of σ1R modulation independent of the opioid system. σ1R knock‐out mice showed attenuated nociceptive responses in the formalin test (Cendán et al., 2005), in sciatic nerve injury (de la Puente et al., 2009), in capsaicin sensitization (Entrena et al., 2009) and in antitumoral‐induced cold and mechanical allodynia (Nieto et al., 2012). …”