Have you ever wondered what happens to the brain of someone who is addicted to drugs, or why they feel pain when going through withdrawal? When it comes to psychostimulants such a cocaine and amphetamine, research has shown that it involves changes in how your neurons are connected, with an amino acid called glutamate (Glu) mediating most of the synaptic transmission between these neurons.1
Figure 1. This displays a glutamatergic synapse, with groups II and III mGluRs located on pre-synaptic neurons and mGluRIs located on post-synaptic neurons.1
Glutamatergic Receptors
There are eight subtypes of metabotropic Glu receptors (mGluRs), and these are grouped into three groups. As seen in Figure 1, group I mGluRs (mGluRIs) are located on post-synaptic neurons and during addiction, are overactive and cause drug-related behaviors by activating phospholipase C. Groups II and III mGluRs are presynaptic autoreceptors that when active, decrease synaptic Glu levels by inhibiting cAMP levels. This then decreases Glu binding to post-synaptic receptors, decreasing the excitatory signals being sent from post-synaptic neurons.1
Cocaine/Psychostimulants Impact on Glutamatergic Signaling
In general, psychostimulants impact the glutamatergic signaling system by increasing the amount glutamate in synapses of the of brain areas involved in learning and memory, which then excites these areas, specifically the ventral tegmental area (see Figure 1), to release dopamine (DA) (for more information on the reward circuit anatomy, click here. DA then causes the perception of pleasure, so when psychostimulants cause DA increase, neurons modify how their connections to other neurons and number of glutamatergic receptors so that more glutamate is present in synapses, reinforcing the use of psychostimulants because we perceive more reward after each dose. Looking specifically at cocaine, it works to increase mGluRIs to increase Glu and DA levels while also decreasing mGluRII levels, which both combined, significantly increases Glu levels and rewires neuronal structure to reinforce cocaine use.1
To learn how other psychostimulants, such as nicotine and amphetamines, impact mGluRs, click here.
Drug Withdrawal & Pain Perception
So that explains why drugs are addictive, but why is trying to get off drugs so painful? Drug withdrawal often involves headaches, vomiting, diarrhea, and/or weakness2, but how stimulation of the pain pathway related to the reward pathway that is so clearly impacted by drug addiction?
To research this, one study investigated the effects of chronic morphine use on cAMP-mediated synaptic actions and pain behaviors, focusing on neurons in the nucleus raphe magnus (NRM) (which is an area of the brainstem involved in opioid modulation of spinal cord pain transmission). Results showed that chronic morphine use increased cAMP levels by activating the enzyme that initiates its formation, causing increased Glu transmission, and that this was accompanied by fewer groups II and III mGluRs. Then, it was found that NRM cells increased the amount of excitatory post-synaptic currents (EPSCs) sent up to the brain to relay pain signals, but only if they contained m-receptors. Notably, cocaine has the exact same impact on the number of groups II and III mGluRs.3
Figure 2. This illustrates one pain perception pathway occurring during drug withdrawal.
Therefore, I have applied the impact of morphine on pain perception during withdrawal to be like that of cocaine. This pathway is seen in Figure 2, but to outline it in words:
- Opioids (morphine) and psychostimulants (cocaine) increase Glu levels and decrease group II mGluRs.
- Increased Glutamate transmission to the NRM
- m-receptor-containing NRM cells relay pain signals to the cortex3
To further solidify m-receptor-containing NRM cells’ role in pain perception, it was shown that patients going through opioid withdrawal experience a more positive hyperpolarization-activated, cyclic nucleotide-gated (HCN) current (Ih). For more information on what this is, click here, but in essence, this caused increased depolarization of m-receptor-containing NRM neurons, thus increasing pain perception during drug withdrawal.3 The firing of these neurons is illustrated in Figure 3.
Figure 3. This displays how inhibition of Ih with ZD7288, an Ih blocker, reduced depolarization of m-receptor-containing NRM cells down to a level similar to control rats, whereas withdrawn rats with ZD7288 administration experienced a higher frequency of action potentials.3
Conclusion
In summary, chronic drug use alters neuronal connections to make it so you perceive maximal amounts of reward when taking said drug, but the increased amounts of glutamate in your synapses also activates receptors involved in pain pathways, leading to the physical pain sensitization characteristic to drug withdrawal. Therefore, further research should be done to see if drugs that decrease excitation of pain pathways can help patients trying to recover from drug addiction but suffering through severe drug withdrawal pain.
Footnotes:
1Mozafari, R., et. al. “A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder.” Progress in Neuropsychopharmacology & Biological Psychiatry, vol. 124, 2022, pp 1-12. doi.org/10.1016/j.pnpbp.2023.110735
2 “Signs, Symptoms, & Causes of Drug Abuse & Withdrawal.” Millcreek Behavioral Health. 2025. https://www.millcreekbehavioralhealth.com/mental-health/addiction/withdrawal-side-effects/
3Bie, B., et. al. “cAMP-Mediated Mechanisms for Pain Sensitization during Opioid Withdrawal.” The Journal of Neurosci, vol. 25, no. 15, 2005, pp. 3824-3832. doi: 10.1523/JNEUROSCI.5010-04.2005
