Along with their well known role in nicotine addiction and autonomic physiology, neuronal nicotinic receptors (nAChRs) also have profound analgesic effects in animal models and humans. This is not a new idea, even in the early 1500s, soon after tobacco was introduced to the new world, its proponents listed pain relief among the beneficial properties of smoking. In recent years, analgesics that target specific nAChR subtypes have shown highly efficacious antinociceptive properties in acute and chronic pain models. To date, the side effects of these drugs have precluded their advancement to the clinic. This review summarizes the recent efforts to identify novel analgesics that target nAChRs, and outlines some of the key neural substrates that contribute to these physiological effects. There remain many unanswered mechanistic questions in this field, and there are still compelling reasons to explore neuronal nAChRs as targets for the relief of pain.
Along with the well-known rewarding effects, activation of nicotinic acetylcholine receptors (nAChRs) can also relieve pain, and some nicotinic agonists have analgesic efficacy similar to opioids. A major target of analgesic drugs is the descending pain modulatory pathway, including the ventrolateral periaqueductal gray (vlPAG) and the rostral ventromedial medulla (RVM). Although activating nAChRs within this circuitry can be analgesic, little is known about the subunit composition and cellular effects of these receptors, particularly within the vlPAG. Using electrophysiology in brain slices from adult male rats, we examined nAChR effects on vlPAG neurons that project to the RVM. We found that 63% of PAG-RVM projection neurons expressed functional nAChRs, which were exclusively of the α7-subtype. Interestingly, the neurons that express α7 nAChRs were largely non-overlapping with those expressing µ-opioid receptors (MOR). As nAChRs are excitatory and MORs are inhibitory, these data suggest distinct roles for these neuronal classes in pain modulation. Along with direct excitation, we also found that presynaptic nAChRs enhanced GABAergic release preferentially onto neurons that lacked α7-nAChRs. In addition, presynaptic nAChRs enhanced glutamatergic inputs onto all PAG-RVM projection neuron classes to a similar extent. In behavioral testing, both systemic and intra-vlPAG administration of the α7 nAChR-selective agonist, PHA-543613, was antinociceptive in the formalin assay. Furthermore, intra-vlPAG α7 antagonist pretreatment blocked PHA-543613-induced antinociception via either administration method. Systemic administration of sub-maximal doses of the α7 agonist and morphine produced additive antinociceptive effects. Together, our findings indicate that the vlPAG is a key site of action for α7 nAChR-mediated antinociception.
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