Roles of prefrontal cortex and paraventricular thalamus in affective and mechanical components of visceral nociception

Abstract

Visceral pain represents a major clinical challenge in the management of many gastrointestinal disorders, eg, pancreatitis. However, cerebral neurobiological mechanisms underlying visceral nociception are poorly understood. As a representative model of visceral nociception, we applied cerulein hyperstimulation in C57BL6 mice to induce acute pancreatitis and performed a behavioral test battery and c-Fos staining of brains. We observed a specific pain phenotype and a significant increase in c-Fos immunoreactivity in the paraventricular nucleus of the thalamus (PVT), the periaqueductal gray, and the medial prefrontal cortex (mPFC). Using neuronal tracing, we observed projections of the PVT to cortical layers of the mPFC with contacts to inhibitory GABAergic neurons. These inhibitory neurons showed more activation after cerulein treatment suggesting thalamocortical "feedforward inhibition" in visceral nociception. The activity of neurons in pancreatitis-related pain centers was pharmacogenetically modulated by designer receptors exclusively activated by designer drugs, selectively and cell type specifically expressed in target neurons using adeno-associated virus-mediated gene transfer. Pharmacogenetic inhibition of PVT but not periaqueductal gray neurons attenuated visceral pain and induced an activation of the descending inhibitory pain pathway. Activation of glutamatergic principle neurons in the mPFC, but not inhibitory neurons, also reversed visceral nociception. These data reveal novel insights into central pain processing that underlies visceral nociception and may trigger the development of novel, potent centrally acting analgesic drugs.

Reticular Formation and Pain: The Past and the Future

“…Hitherto, optogenetics have been successfully used to study brain circuits such as those involved in regulation of the sensory and affective aspects of pain, namely cortico-limbic networks (Copits et al, 2016). Chemogenetics have also been successfully used to examine spinal circuits involved in pain modulation (Bourane et al, 2015; Peirs et al, 2015; Saloman et al, 2016) and the study of descending pain modulation is also starting to be approached by both technologies (Cai et al, 2014; Hickey et al, 2014; Jurik et al, 2015; Li et al, 2016). The RF contains areas relaying and integrating nociceptive information, from the brain and the spinal cord with other physiological functions.…”

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex

“…One possible explanation of this local effect of ethanol is activation of the descending nociceptive facilitation pathway [47]. It is interesting to note that neuronal activity in the mPFC, especially the PrLC and ILC, can be inhibited by a GABAergic enhancing mechanism under some pathological pain conditions in animal models of joint arthritis, peripheral neuropathy, and visceral pain [14,[48][49][50]. Moreover, deactivation of excitatory neurons in the PrLC via Cdk5 (cyclin-dependent kinase 5) promotes pain sensation and anxiety [13].…”

“…Moreover, deactivation of excitatory neurons in the PrLC via Cdk5 (cyclin-dependent kinase 5) promotes pain sensation and anxiety [13]. In contrast, optogenetic activation of excitatory pyramidal neurons in the PrLC reverses the GABA-mediated inhibitory state, improving both the sensory and affective aspects of pain [13,14,50,51]. Besides, pharmacological activation of the ILC output with a combination of metabotropic glutamate receptor 5 (mGluR5) and cannabinoid receptor type 1 (CB1) activators inhibits pain-related behavior and restores decisionmaking in an arthritis model of pain [52].…”

Usefulness of knockout mice to clarify the role of the opioid system in chronic pain

“…The administration of CNO will decrease or increase the activity of this specific neuronal circuit depending on the signalling cascade coupled to the designer receptor expressed (Whissell et al, ). These techniques have been used to clarify the specific involvement of different spinal cord neuronal populations in itch (Bourane et al, ), acute (Peirs et al, ; Saloman et al, ) and chronic pain (Peirs et al, ), and supraspinal circuits of visceral pain (Jurik et al, ). However, none of these studies has yet examined the function of the endogenous opioid system in chronic pain conditions.…”