Search

Background: Preclinical assays of affective and sensorial aspects of nociception play a key role in research on both the neurobiology of pain and the development of novel analgesics. Therefore, we investigated the effects of nicotine and alpha-7 nicotinic acetylcholine receptor (nAChR) modulators in the negative affective and sensory components of visceral pain in mice.Methods and Results: Intraperitoneal acetic acid (AA) administration resulted in a robust stretching behaviour and conditioned place aversion (CPA) in mice. We observed a dose-dependent reduction in AA-induced stretching and CPA by the nonselective nAChRs agonist nicotine. Mecamylamine, a nonselective nAChRs agonist, was able to block its effects; however, hexamethonium, a peripherally restricted nonselective nicotinic antagonist, was able to block nicotine's effect on stretching behaviour but not on CPA. In addition, systemic administration of α7 nAChR full agonists PHA543613 and PNU282987 was failed to block stretching and CPA behaviour induced by AA. However, the α7 nAChR-positive allosteric modulator PNU120596 blocked AA-induced CPA in a dose-dependent manner without reducing stretching behaviours.Conclusions: Our data revealed that while nonselective nAChR activation induces antinociceptive properties on the sensorial and affective signs of visceral pain in mice, α7 nAChRS activation has no effect on these responses. In addition, nonselective nAChR activation-induced antinociceptive effect on stretching behaviour was mediated by central and peripheral mechanisms. However, the effect of nonselective nAChR activation on CPA was mediated centrally. Furthermore, our data suggest a pivotal role of allosteric modulation of α7 nAChRS in the negative affective, but not sensory, component of visceral pain.Significance: The present results suggest that allosteric modulation of α7 nAChR may provide new strategies in affective aspects of nociception. [ABSTRACT FROM AUTHOR]

Background and Purpose: The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception.Experimental Approach: We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception.Key Results: Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ).Conclusions and Implications: Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation.Linked Articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. [ABSTRACT FROM AUTHOR]

Background and Purpose: The α7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that α7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the α7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II α7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model.Experimental Approach: We assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective α7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice.Key Results: We found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and α7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of α7 nAChRs.Conclusions and Implications: Our results demonstrate that type II α7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous α7 agonist choline. [ABSTRACT FROM AUTHOR]

Background and purpose: Adenylyl cyclase sensitization occurs on chronic agonist activation of µ-opioid receptors and is manifested by an increase in cAMP levels (overshoot) on challenge with antagonist. It has been proposed that a long lasting constitutively active receptor is formed on chronic µ-opioid exposure and that antagonists with inverse agonist activity rapidly return the receptor to a basal state causing a cAMP overshoot and a more severe withdrawal response in vivo. This hypothesis depends on an accurate characterization of neutral and inverse agonist properties of opioid antagonists. Experimental approach: C6 glioma and HEK293 cells expressing µ-opioid receptors were used. Opioid antagonists were examined for their ability to induce a cAMP overshoot following chronic treatment with the agonist DAMGO ([D-Ala2,N-Me-Phe4,Glyol5]-enkephalin). The compounds were also characterized as agonists, inverse agonists or neutral antagonists by using assays for competitive binding, [35S]GTPγS (guanosine-5′-O-(3-[35S]thio)triphosphate) binding and changes in cell surface receptor expression. Key results: Naltrexone, 6β-naltrexol and naloxone were indistinguishable to the µ-opioid receptor in the opioid-naïve or dependent state and acted as neutral antagonists. The δ-opioid receptor inverse agonist RTI-5989-25 [(+)- N-[ trans-4′-(2-methylphenyl)-2′-butenyl]-(3 R,4 R)-dimethyl-4-(3-hydroxyphenyl)piperidine], a 3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine, was an inverse agonist at the µ-opioid receptor, and the peptide antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) showed variable, assay-dependent properties. All the antagonists precipitated the same degree of cAMP overshoot in opioid-dependent cells. Conclusions and implications: Antagonists at the µ-opioid receptor may be neutral or show inverse agonist activity. Formation of a constitutively active µ-opioid receptor is not a requirement for the development or expression of adenylyl cyclase sensitization. [ABSTRACT FROM AUTHOR]