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

Abstract

Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans. Human neuroimaging studies suggest that alcohol dependence and chronic pain may share common mechanisms through amygdala-medial prefrontal cortex (mPFC) interactions. However, whether acute administration of ethanol in the mPFC can modulate pain perception is unknown. Here we showed that bilateral microinjections of ethanol into the prelimbic and infralimbic areas of the mPFC lowered the bilateral mechanical pain threshold for 48 h without influencing thermal pain sensitivity in adult rats. However, bilateral microinjections of artificial cerebrospinal fluid into the mPFC or bilateral microinjections of ethanol into the dorsolateral PFC (also termed as motor cortex area 1 in Paxinos and Watson's atlas of The Rat Brain. Elsevier Academic Press, Amsterdam, 2005) failed to do so, suggesting regional selectivity of the effects of ethanol. Moreover, bilateral microinjections of ethanol did not change the expression of either pro-apoptotic (caspase-3 and Bax) or anti-apoptotic (Bcl-2) proteins, suggesting that the dose was safe and validating the method used in the current study. To determine whether c-aminobutyric acid A (GABA A ) receptors are involved in mediating the ethanol effects, muscimol, a selective GABA A receptor agonist, or bicuculline, a selective GABA A receptor antagonist, was administered alone or co-administered with ethanol through the same route into the bilateral mPFC. The results showed that muscimol mimicked the effects of ethanol while bicuculline completely reversed the effects of ethanol and muscimol. In conclusion, ethanol increases mechanical pain sensitivity through activation of GABA A receptors in the mPFC of rats.

Empathy for Distress in Humans and Rodents

“…This result is similar to that of empathy for pain or distress in rats [11]. Moreover, the same treatment with bicuculline (20 lmol/ L), a GABAA receptor antagonist, in the bilateral mPFC blocked the development of mechanical pain hypersensitivity and enhancement of BV-induced pain-related behavioral response produced by bilateral microinjections of ethanol and muscimol, supporting a role of the GABAA receptor in mediating both oxytocin and ethanol at the mPFC in the development of empathy for pain or distress in rodents [15].…”

“…Because empathy is thought to be produced only among familiars, the physician's ability to empathize during patient/patient's kinship-physician interactions would be very important and necessary for establishing a physician-patient rapport, a fusion of the empathic bubbles of the patient/patient's kinship and the physician (and nurses/hospital staff). This proposition is strongly supported by a well-designed experimental report showing that a physician's high perspective-taking scores (skills) are highly correlated with increased activity of the rostral anterior cingulate cortex (rACC) during patient-physician interaction [7], an area that has been demonstrated to be a key brain region for the mediation of both vicariously felt pain (empathy for pain) and emotional response to directly experienced pain in both humans [8][9][10] and animals [11][12][13][14][15](for review see [16]).…”

“…It has been proposed that acute alcohol consumption and intranasal oxytocin have a common effect on emotion, social cognition, and behavior through acting on limbic and prefrontal cortical structures in humans, resulting in an enhancement of empathy-based altruism such as helping motivation, trust, generosity, and morality [126]. Microinjections of both ethanol (20 mmol/L or 90 mg/dL, equivalent to a peak blood concentration of 1.0 g/kg, defined as moderate consumption) and muscimol (5 mmol/ L), a c-aminobutyric acid A (GABAA) receptor agonist, in a volume of 0.5 lL into the bilateral mPFC of rats resulted in mechanical pain hypersensitivity and enhancement of BV-induced pain-related behavioral responses but without affecting thermal pain sensitivity [15]. This result is similar to that of empathy for pain or distress in rats [11].…”

A Context-Based Analgesia Model in Rats: Involvement of Prefrontal Cortex

“…For example, in a rat model of empathy for pain, which is also dependent on the PL/IL cortices, only mechanical pain hypersensitivity can be demonstrated while thermal pain sensitivity remains unchanged [ 37 , 38 ]. Intra-PL/IL administration of ethanol has also been demonstrated to result in mechanical pain hypersensitivity but with unchanged thermal pain sensitivity [ 39 ].…”

Synaptic Homeostasis and Allostasis in the Dentate Gyrus Caused by Inflammatory and Neuropathic Pain Conditions

“…However, it remains poorly understood how this imbalance (allostasis) develops in the CNS under different pain conditions. In our and others’ previous reports, the limbic system including the medial prefrontal cortex, the hippocampal formation (HF) and amygdala has been demonstrated to be highly involved in emotional, cognitive and social modulation of pain (Ren et al, 2008 ; Neugebauer et al, 2009 ; Lyu et al, 2013 ; Li et al, 2014 ; Neugebauer, 2015 ; Geng et al, 2016 ; Lu et al, 2016 ; for reviews see Liu and Chen, 2009 , 2014 ). Synaptic plasticity at both excitatory and inhibitory synapses serves as an important universal mechanism underlying pain-associated emotional and cognitive deficits (Zhao et al, 2009 ; Gong et al, 2010 ; Liu et al, 2011 , 2012 ; Lu et al, 2014 ; for reviews see Liu and Chen, 2009 , 2014 ).…”