ns-9283 and Pain

Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4β2 receptors being the most abundant heteromer. The stoichiometry of α4β2 receptors can be either (α4)(3)(β2)(2) or (α4)(2)(β2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4β2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4β2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4β2 nAChR in rotational and analgesic responses and confirm striatal α4β2 receptors to be of the HS form.

Topics: Allosteric Regulation; Animals; Azepines; Corpus Striatum; Female; Male; Nicotinic Agonists; Oxadiazoles; Oxidopamine; Pain; Pain Measurement; Parkinsonian Disorders; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Nicotinic; Rotation

Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4β2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 μmol/kg, i.p.) induced a 6-fold leftward shift of the dose-response of ABT-594 (ED(50)=26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED(50)=26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED(50)=1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose-response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 μmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4β2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4β2 nAChR by PAM may represent a novel analgesic approach.

Topics: Allosteric Regulation; Analgesics; Animals; Azetidines; Behavior, Animal; Body Temperature; Brain; Disease Models, Animal; Drug Therapy, Combination; Magnetic Resonance Imaging; Male; Nicotinic Agonists; Osteoarthritis; Oxadiazoles; Pain; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic