Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models
Highlights
► Alpha7 positive allosteric modulators are anti-inflammatory. ► PNU-120596 reversed carrageenan-induced thermal hyperalgesia and paw edema. ► PNU-120595 anti-inflammatory effects were α7 receptor-mediated. ► NS1738 did not attenuate hyperalgesia and allodynia in the CCI model. ► PNU-120596 reversed thermal hyperalgesia and allodynia in the CCI model.
Introduction
Chronic neuropathic pain arguably arises due to long-term plasticity changes in somatosensory pathways from the periphery to the cortex. These plasticity changes often occur after nerve injury and/or dysfunction in the central nervous system (CNS), resulting in significantly enhanced pain sensation (hyperalgesia) or in otherwise non-noxious stimuli to cause pain (allodynia) (Wang et al., 2011; Zhou, 2007; Harden, 2005). Increased pain sensitivity, one of the most common signs of an inflammatory disorder, is mediated by a host of different factors, including enzymes, neuropeptides, eicosanoids, chemokines and cytokines (Dray and Bevan, 1993; Sandkuhler, 2009; Wang et al., 2011). To date, several drugs, such as opioids and anti-inflammatory, anti-seizure and antidepressant agents, used to treat chronic neuropathic pain have major adverse effects and/or incomplete pain relief for patients. Thus, development of drugs possessing increased efficacy and safety is needed.
Previous studies suggest utility of nicotinic acetylcholine receptor (nAChR) agonists to treat chronic pain conditions (Bannon et al., 1998; Khan et al., 2003; Miao et al., 2004; Vincler, 2005; Pacini et al., 2010). Multiple subtypes of nAChRs are expressed in pain transmission pathways (Khan et al., 2003). For example, α4β2* and α7 subtypes are expressed in the spinal cord dorsal horn (Cordero-Erausquin et al., 2004; Cordero-Erausquin and Changeux, 2001; Marubio et al., 1999). Recent work has focused on the role of the α7 nAChRs in modulating inflammation and nociception (Westman et al., 2010; Marrero and Bencherif, 2009; Medhurst et al., 2008; de Jonge and Ulloa, 2007). In addition to their neuronal presence, α7 nAChRs are expressed on macrophages (Tracey, 2002; Wang and Wang, 2003; Ulloa, 2005), which are key immune cells involved in the initiation, maintenance, and resolution of inflammation (Fujiwara and Kobayashi, 2005). Previous studies have demonstrated the importance of acetylcholine (ACh) directly interacting with α7 nAChRs expressed on macrophages and other cytokine-producing cells in down-regulating proinflammatory cytokine synthesis and preventing tissue damage (Tracey, 2002; De Rosa et al., 2009; Wang et al., 2009). In addition, Xiao et al. (2002) showed an up-regulation of α7 nAChR subunit expression in the rat dorsal root ganglion fourteen days after sciatic nerve axotomy. Moreover, α7 nAChRs agonists elicited significant anti-inflammatory and antinociceptive effects in rodent models of chronic neuropathic pain and inflammation (Damaj et al., 2000; Wang et al., 2005; Hamurtekin and Gurun, 2006; Medhurst et al., 2008; Gurun et al., 2009; Rowley et al., 2010). Therefore, the α7 nAChR represents a promising target for the development of analgesic and anti-inflammatory agents. However, concerns regarding α7 nAChR agonists as clinical candidates persist. For example, α7 nAChRs desensitize rapidly in response to high agonist concentration in vitro followed by a long period of desensitization (Bertrand et al., 1992). Furthermore, an agonist-based therapeutic approach would disrupt endogenous cholinergic tone (Papke et al., 2009).
One alternative approach to selectively enhance activity of the α7 nAChRs is via positive allosteric modulation. As reported previously (Faghih et al., 2007), positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy and potency of an agonist without directly stimulating the agonist-binding sites. In principle, PAMs do not exhibit intrinsic activity at the receptor, however they can reinforce endogenous cholinergic neurotransmission without directly activating α7 nAChRs (Albuquerque et al., 2001; Faghih et al., 2007, 2008). PAMs have been classified as either type I, such as NS1738, or type II, such as PNU-120596, on the basis of their distinct effects on desensitization (Bertrand and Gopalakrisshnan, 2007; Bertrand et al., 2008; Timmermann et al., 2007). PNU-120596, but not NS1738, modifies the equilibrium among active and desensitized states resulting in significantly prolonged responses, even promoting the activation of previously desensitized receptors (Grønlien et al., 2007; Hurst et al., 2005; Roncarati et al., 2008). Initially, allosteric modulators of the α7 nAChRs were developed for the treatment of cognitive disorders such as Alzheimer's disease and schizophrenia, however their effects in pain models have not been reported (Ahring et al., 2007; Faghih et al., 2007; Conejero-Goldberg et al., 2008; McLean et al., 2012).
Therefore, in the present study, we evaluated whether potentiating the endogenous α7 cholinergic system through the allosteric modulation of α7 nAChRs produces anti-inflammatory, anti-hyperalgesic and anti-allodynic effects in mouse models of inflammation and chronic neuropathic pain. Accordingly, NS1738 (a type I α7 nAChR PAM) and PNU-120596 (a type II α7 nAChR PAM) were evaluated in the carrageenan short-term inflammatory pain and the chronic constriction injury (CCI) neuropathic pain models. In addition, we evaluated whether PNU-120596 enhances the antinociceptive effects of a selective α7 nAChRs agonist, PHA-543611, in these models.
Section snippets
Subjects
Naïve male adult ICR (Harlan Laboratories; Indianapolis, IN) mice weighing between 20 and 30 g served as subjects. Mice were housed 4–5 per cage in a temperature-controlled (20–22 °C) environment with a 12-h light–dark cycle and were given unlimited access to food and water in their home cages. All animals were maintained in a facility approved by the American Association for Accreditation of Laboratory Animal Care and the study was approved by the Institutional Animal Care and Use Committee of
Effect of NS1738 and PNU-120596 in the carrageenan test
Mice were given an intraplantar injection of carrageenan and then tested for hyperalgesia and edema 6 h later. Anti-hyperalgesic and anti-edematous effects of the α7 nAChRs PAMs were determined after i.p. administration of the drugs. The administration of 10 and 30 mg/kg of NS1738 15 min before intraplantar carrageenan blocked the development of hyperalgesic responses [F(2,27) = 9.07, p < 0.01] (Fig. 1A). The anti-hyperalgesic effect of NS1738 at 30 mg/kg was blocked by pretreating the animals
Discussion
The objective of the present study was to examine the effects of type I (NS1738) and II (PNU-120596) α7 nAChR PAMs in murine inflammatory and chronic neuropathic pain models after acute administration. Overall, our results showed that while both NS1738 and PNU-120596 attenuated hyperalgesia associated with inflammation, only PNU-120596 decreased the hyperalgesia and allodynia in the chronic neuropathic pain model. Whereas PNU-120596 produced consistent effects in carrageenan and CCI models,
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