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Medial Prefrontal Cortex Endocannabinoid Signalling and Modulation of Neuropathic Pain through Descending Control

Published: 31/01/2024

Chronic pain is recognised to activate several brain areas, which underlies affective aspects of the pain experience. For example, the medial prefrontal cortex (mPFC) is a critical brain area in pain processing that receives ascending nociceptive input and exerts top-down control of pain sensation. In the context of pain, both the rat and human mPFC receive innervation from the thalamus, which in turn receives nociceptive input from the peripheral nervous system via the spinal cord. Previous studies have revealed a dynamic change in endocannabinoid-dependent mPFC activity after painful peripheral nerve injury.

Endocannabinoid signalling has been shown to regulate mPFC activity through the cannabinoid receptor type 1 (CB1R). Previous findings reveal that CB1R activation suppresses inhibitory input to the mPFC, and this signalling pathway becomes hyperactive after spared nerve injury. However, over time, CB1R-dependent disinhibition of the mPFC is lost, and mPFC activity becomes hypoactive in the chronic phase of neuropathic pain. It is therefore possible that manipulating mPFC endocannabinoid signalling in different phases of neuropathic pain may alter descending inhibition of nociceptive signals. To test this theory, the authors of a recent study used pharmacological, behavioural, and electrophysiological approaches to evaluate the involvement of mPFC endocannabinoid signalling in the modulation of descending pain control.

Design and Methods of the Study

A total of 136 male and female Sprague-Dawley rats were used in this study in which some rats were subject to spared nerve injury surgery. Control rats received sham surgery in the form of skin incision, nerve exposure, and closure only.

Behavioural Tests

Sensory testing of the plantar skin involved evoking reflexive behaviours by punctate mechanical stimulation at threshold intensity (von Frey test) and at noxious intensity (pin test), by dynamic non-noxious mechanical stimulation (brush test), and cold stimulation (acetone test).

The von Frey test involved the use of thin calibrated plastic filaments applied to the plantar surface of the hind paw and assessing the level that determines a hind paw withdrawal response.

The pin test applied a needle to the central portion of the hind paw with enough force to indent the skin but not puncture it.

The cold stimulation (acetone) test was tested by applying acetone to the lateral plantar skin. The response was scored as positive if the paw was removed.

The brush test was assessed through applying a light stroke to the lateral plantar skin of the hind paw by over 2 seconds. A positive test is characterised by removal of the paw in response to a light stroke.

To assess mPFC CB1R activity on the transmission signals up the spinal nociceptive pathways, the researchers injected WIN-55,212-2 (a potent CB1R agonist) into the mPFC to activate CB1Rs in that region selectively. The authors then recorded activity in dorsal horn wide-dynamic-range neurons, which transmit nociceptive information between sensory neurons and the brain.

Results of the Study

This study found that inhibition of CB1Rs in the acute phase following spared nerve injury helped to reduce the development of chronic pain. This suggests that endocannabinoid-dependent mechanisms in the mPFC are related to the development of chronic pain.

The researchers also found that activation of CB1R in the chronic phase after spared nerve injury in the mPFC reversed pain-like behaviours through activation of descending inhibitory signals down the spinal cord.

This is coupled with new observations that also indicate that cortical sites may also be involved with regulating pain at the dorsal horn level, in addition to the mPFC. These results also align with behavioural data and electrophysiological recordings, which support the notion that functional changes of mPFC can modulate descending control of pain. However, the current study has helped to illuminate the role of the endocannabinoid system in the mPFC in descending pain modulation.

In conclusion, either activation of CB1R in the mPFC in the chronic phase of pain, or blockade of CB1R in the acute phase of pain increased descending nociceptive inhibition. This supports the hypothesis that the endocannabinoid system signalling in the mPFC plays an important role in the development and maintenance of chronic pain.

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