Nicotinic modulation of descending pain control circuitry

Abstract

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.

Hypersensitivity of Prelimbic Cortex Neurons Contributes to Aggravated Nociceptive Responses in Rats With Experience of Chronic Inflammatory Pain

“…Functional and structural connectivity between PAG and mPFC relates to individual differences in attention to pain (Kucyi et al, 2013 ). PAG is a critical component of the descending pain modulatory system, and usually exerts an inhibitory effect on nociceptive transmission (Umana et al, 2017 ). Evidence shows that glutamatergic projections from mPFC act to inhibit PAG function (Franklin et al, 2017 ).…”

“…Excitability of layer 4/5 pyramidal neurons in the PL increases in complete Freund’s adjuvant (CFA)-induced inflammatory mice (Wu et al, 2016 ), and bilateral lesions of the PL attenuate CFA-induced heat hyperalgesia (Wang et al, 2015 ). PL may regulate pain through its projections to a number of other brain areas (Kucyi et al, 2013 ; Khan et al, 2014 ; Yu et al, 2014 ; Lee et al, 2015 ; Vachon-Presseau et al, 2016 ), including amygdala, nucleus accumbens (NAc), hippocampus and in particular periaqueductal gray (PAG), a critical component of the descending pain modulatory system (Umana et al, 2017 ).…”

Nicotine and sleep deprivation: impact on pain sensitivity and immune modulation in rats

“…Recently, Umana et al . has shown that 63% of the projections from vlPAG to the rostral ventromedial medulla express α7 nicotinic acetylcholine receptors (nAChR), suggesting a model of α7 nAChR-mediated analgesia in the vlPAG 26 . In their study, systemic and intra-vlPAG administration of an α7 nAChR-selective agonist showed an antinociceptive effect in the formalin assay, which was blocked by intra-vlPAG α7 antagonist pretreatment 27 .…”

“…Taken together the evidence from the literature, we can speculate that in our study PSD overcame the antinociceptive effects of nicotine pretreatment by inhibiting the pain inhibitory descending vlPAG pathway through A2A receptor activation and D2 receptor inhibition in the nucleus accumbens 27 . Possibly, the antinociceptive effects of nicotine involved multiple pathways, including activation of α4β2 nAChRs 29 and of spinal A2A receptors 36 , release of opioids at the spinal cord 30 as well as nucleus accumbens activation with projections to vlPAG through α7 nAChR 26 .…”

Mechanistic bases for the adverse interaction of nicotine and chronic pain

“…It is possible that this antinociception may reflect an action at α7 nAChRs, modest levels of which are present in these nuclei [189,236,237]. Indeed, others have demonstrated that microinjection of a positive allosteric modulator or a selective α7 nAChR agonist in the PAG produces antinociception in the formalin test [254]. Future studies will utilize other selective antagonists, such as MLA, to better characterize the receptor through which epibatidine is exerting its effects in the PAG.…”