The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking

Abstract

In this study, the use-dependent, nicotinic receptor antagonist bis (2, 2, 6, 6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was evaluated for its ability to attenuate the adverse consequences associated with morphine in rats in all three phases of an abstinence model of drug seeking: self-administration, acute withdrawal, and delayed test of drug seeking. Rats were allowed to self-administer morphine (FR1 schedule) with an active response lever, on a 24hr basis inside operant chambers, for 14 days. Each rat was subsequently evaluated for stereotypical behaviors associated with spontaneous morphine withdrawal. Rats were then placed in standard housing cages for a six week period of protracted abstinence from morphine. After this period, each rat was placed back into its respective operant chamber for a 14 day assessment of unrewarded drug seeking responses. BTMPS was administered to the animals in all three clinically relevant phases in three separate sets of experiments. BTMPS treatment during the self-administration phase resulted in up to a 34% reduction of lever responses to morphine when compared to vehicle treated control animals, as well as a 32% reduction in the dose of morphine self-administered. When given during self-administration and acute withdrawal, BTMPS treatment decreased acute withdrawal symptoms (up to 64%) of morphine use and reduced (up to 45%) drug seeking responses after six weeks of protracted withdrawal compared to control animals. BTMPS treatment after six weeks of abstinence from morphine had no effect. These results offer insight into the role of central cholinergic receptors in the onset and maintenance of drug addiction.

The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies

“…the BXD RI mice. Our findings complement previous findings with non-selective nicotinic antagonists, mecamylamine and BTMPS (Hall et al, 2011;Taraschenko et al, 2005), and with 18-MC, a moderately selective α3β4* nACh receptor antagonist, which have been shown previously to reduce morphine physical dependence signs in rats . The importance of the α3β4* nACh receptor subtype in morphine physical dependence is highlighted by the observation that α4β2* nACh receptors, the major heteromeric subtype expressed in the CNS, do not participate in morphine somatic withdrawal signs.…”

“…The pharmacological results were supported by the data obtained in β4 nACh receptor KO mice, demonstrating a significant reduction of total somatic signs compared with their WT littermates, and by the correlation results with brain α3, α5 and β4 nACh receptor subunit mRNA levels in the BXD RI mice. Our findings complement previous findings with non‐selective nicotinic antagonists, mecamylamine and BTMPS (Hall et al ., ; Taraschenko et al ., ), and with 18‐MC, a moderately selective α3β4* nACh receptor antagonist, which have been shown previously to reduce morphine physical dependence signs in rats (Taraschenko et al ., ). The importance of the α3β4* nACh receptor subtype in morphine physical dependence is highlighted by the observation that α4β2* nACh receptors, the major heteromeric subtype expressed in the CNS, do not participate in morphine somatic withdrawal signs.…”

“…Recent rodent studies demonstrated that the administration of nicotinic antagonists attenuates signs of morphine withdrawal. For example, the non‐selective nicotinic antagonists, mecamylamine and bis (2, 2, 6, 6‐tetramethyl‐4‐piperidinyl) sebacate (BTMPS), were found to attenuate both spontaneous and naloxone‐precipitated somatic signs in rats undergoing morphine withdrawal (Taraschenko et al ., ; Hall et al ., ). One particular nACh receptor subtype that has been indicated in decreasing somatic signs in precipitated morphine withdrawal is the α3β4* nACh receptor subtype (where * denotes the possible inclusion of additional subunits, see Alexander et al ., 2013).…”

Contact allergy to Tinuvin 770, a hindered amine light stabilizer in sandals contributing to hyperkeratotic foot dermatitis

“…The mechanism of action of a HALS on radicals is shown in Figure S2. Tinuvin 770 reportedly has L‐type Ca 2+ ‐channel blocker activity, and has thus been studied as an inhibitor of various receptors, and the hazards associated with Tinuvin 770 have been previously studied . The binding of HALSs to proteins was examined, but no effect was found .…”

“…Tinuvin 770 reportedly has L-type Ca 2+ -channel blocker activity, and has thus been studied as an inhibitor of various receptors, and the hazards associated with Tinuvin 770 have been previously studied. [7][8][9][10][11][12][13][14][15][16] 16 The binding of HALSs to proteins was examined, but no effect was found. 17 To our knowledge, this is the first report of allergic dermatitis caused by a HALS.…”