, 2002). Thus, it may not necessarily be the case that the opposite behavior to that induced by antidepressant treatments selleck chemical (i.e., decreased immobility) necessarily reflects a depression-like state. ��4-Containing nAChRs in Nociception Our data show a role for ��4-containing nAChRs in the analgesic effects of nicotine. ��4 subunits contributing to nicotine-induced analgesia may be located in the brain and spinal cord because deletion of ��4 subunits in the knockout mice affected both reflex and integrated responses to noxious heat. ��4 subunits have a restricted pattern of expression in the brain, with notable enrichment in the habenulo�Cpeduncular tract (Gahring et al., 2004). Interestingly, nicotine microinjection into the interpeduncular nucleus produces analgesia in a rat model of acute thermal pain (Hamann & Martin, 1992).

At the spinal level, ��4 subunits are expressed presynaptically on primary afferents in the superficial layer of the dorsal horn (Khan et al., 2003), but nAChRs expressed on primary afferent terminals have been implicated in the pronociceptive, rather than antinociceptive, effect of nicotinic agonists (Khan et al., 2004). The ��4 subunit belongs to a genomic cluster together with the ��3 and ��5 subunits, and these three subunits co-assemble into functional receptors (Boulter et al., 1990; Wang et al., 1996). Interestingly, deletion of ��5 subunits also decreases the antinociceptive effects of nicotine in models of acute thermal pain, and the ��3 and ��5 subunits also display strikingly high expression in the habenulo�Cpeduncular pathway (Boulter et al.

, 1990; Jackson et al., 2010; Salas et al., 2004a; Wada et al., 1989). It can be hypothesized that activation of ��3��5��4 nAChRs expressed in the habenula or interpeduncular nucleus produces analgesia because some habenular neurons respond to noxious input (Dafny & Qiao, 1990), and habenular stimulation has analgesic effects (Cohen & Melzack, 1986). While acute administration of nicotine produces analgesia, spontaneous or antagonist-precipitated withdrawal from chronic nicotine exposure induces hyperalgesia (Damaj, Kao, & Martin, 2003). Interestingly, nicotine withdrawal-induced hyperalgesia is also abolished in ��4?/? AV-951 mice (Salas et al., 2004b). The ��4 subunit therefore plays a central role in the modulation of nociceptive thresholds by nicotine, contributing to both nicotine-induced analgesia and the counter adaptive increase in pain sensitivity during nicotine withdrawal. Conclusions Overall, our findings provide insights into the role of ��4-containing nAChRs in cognitive function, affective behaviors, and nociception.