Sex differences in the potency of κ opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats

Lomas, Lisa M.; Barrett, Andrew C.; Terner, Jolan M.; Lysle, Donald T.; Picker, Mitchell J.

doi:10.1007/s00213-006-0663-1

Cited by 23 publications

(21 citation statements)

References 34 publications

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“…In the present study, the mu agonists nalbuphine, morphine, and methadone all produced dose-dependent decreases in rates of schedule-controlled responding and increases in thermal antinociception consistent with previously published studies (Dykstra and Woods, 1986;Gerak et al, 1994;Gatch et al, 1995Gatch et al, , 1998Stevenson et al, 2003). This is the first study to describe the antiallodynic effects of nalbuphine in nonhuman primates, although nalbuphine was shown to be effective in some rat models of inflammatory pain (Lomas et al, 2007;Ortiz et al, 2007;Ortiz and Castañ eda-Herná ndez, 2008). Clomipramine produced little or no effect up to the highest dose tested in all three assays, which agrees with previous studies in finding that clomipramine and other serotonin uptake inhibitors produce little effect on rates of schedule-controlled responding or thermal nociception in nonhuman primates (Kleven and Woolverton, 1993;Spealman, 1993;Gatch et al, 1998) or pain-related behaviors in rodent models of inflammatory pain (Pedersen et al, 2005).…”

Section: Discussionsupporting

confidence: 91%

Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy

Banks

Rice²,

Negus³

2010

J Pharmacol Exp Ther

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Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine Ͻ morphine Ͻ methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine Ͼ morphine Ͼ methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

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Section: Discussionsupporting

confidence: 91%

Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy

Banks

Rice²,

Negus³

2010

J Pharmacol Exp Ther

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“…The drugs [D-Ala 2 , N-Me-Phe 4 , Gly 5 -ol]-Enkephalin acetate salt (1) (DAMGO, 5 µg/paw); [D-Pen 2,5 , p-Cl-Phe 4 ]-Enkephalin (DPDPE, 20 µg/paw); (−)- trans -(1S,2S)-U-50488 hydrochloride hydrate (U 50,488, 10 µg/paw) [23]; Prostaglandin E 2 (PGE 2 , 100 ng/paw) [23], [24]; D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP, 20 µg/paw) [25], [26], nor-binaltorphimine dihydrochloride (nor-BNI, 50 µg/paw) [25], [27]; N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI 174,864, 10 µg/paw) [25], methiodide naloxone (1 mg/Kg, subcutaneously) were used in this study [28]. These drugs were purchased from Sigma-Aldrich, Saint Louis, MO, USA.…”

Section: Methodsmentioning

confidence: 99%

Peripheral Sensitization Increases Opioid Receptor Expression and Activation by Crotalphine in Rats

et al. 2014

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Inflammation enhances the peripheral analgesic efficacy of opioid drugs, but the mechanisms involved in this phenomenon have not been fully elucidated. Crotalphine (CRP), a peptide that was first isolated from South American rattlesnake C.d. terrificus venom, induces a potent and long-lasting anti-nociceptive effect that is mediated by the activation of peripheral opioid receptors. Because the high efficacy of CRP is only observed in the presence of inflammation, we aimed to elucidate the mechanisms involved in the CRP anti-nociceptive effect induced by inflammation. Using real-time RT-PCR, western blot analysis and ELISA assays, we demonstrate that the intraplantar injection of prostaglandin E2 (PGE2) increases the mRNA and protein levels of the µ- and κ-opioid receptors in the dorsal root ganglia (DRG) and paw tissue of rats within 3 h of the injection. Using conformation state-sensitive antibodies that recognize activated opioid receptors, we show that PGE2, alone does not increase the activation of these opioid receptors but that in the presence of PGE2, the activation of specific opioid receptors by CRP and selective µ- and κ-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the δ-opioid receptor. CRP increased the level of activated mitogen-activated protein kinases in cultured DRG neurons, and this increase was dependent on the activation of protein kinase Cζ. This CRP effect was much more prominent when the cells were pretreated with PGE2. These results indicate that the expression and activation of peripheral opioid receptors by opioid-like drugs can be up- or down-regulated in the presence of an acute injury and that acute tissue injury enhances the efficacy of peripheral opioids.

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“…However, this should not be interpreted to mean that μ opioid receptor agonists are antinociceptive in males and κ opioid receptor agonists are antinociceptive in females. Two recent studies51,52 examined κ receptor agonists in rats and mice and found that males had a greater response than females. This response contradicts earlier work17,47–49 and is similar to the antinociceptive response of rodents to μ receptor agonists.…”

Section: Animal Modelsmentioning

confidence: 99%

Sex, Gender, and Pain: An Overview of a Complex Field

Hurley

Adams

2008

Anesthesia &Amp; Analgesia

217

140

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Traditionally, biomedical research in the field of pain has been conducted with male animals and subjects. Over the past 20–30 yr, it has been increasingly recognized that this narrow approach has missed an important variable: sex. An ever-increasing number of studies have established sex differences in response to pain and analgesics. These studies have demonstrated that the differences between the sexes appear to have a biological and psychological basis. We will provide brief review of the epidemiology, rodent, and human experimental findings. The controversies and widespread disagreement in the literature highlight the need for a progressive approach to the questions involving collaborative efforts between those trained in the basic and clinical biomedical sciences and those in the epidemiological and social sciences. In order for patients suffering from acute and/or chronic pain to benefit from this work, the approach has to involve the use or development of clinically relevant models of nociception or pain to answer the basic, but complex, question. The present state of the literature allows no translation of the work to our clinical decision-making.

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Sex differences in the potency of κ opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats

Abstract: These findings demonstrate sex differences in kappa opioid activity in a persistent pain model. Although an NMDA antagonist blocked the effects of kappa opioids in this model, these effects were not sexually dimorphic as reported in most acute pain models.

Cited by 23 publications

References 34 publications

Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy

Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy

Peripheral Sensitization Increases Opioid Receptor Expression and Activation by Crotalphine in Rats

Sex, Gender, and Pain: An Overview of a Complex Field

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