NIDA Notes

Novel Compound Alleviates Hard-to-Treat Pain in Mice

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By William Ross Perlman, Ph.D., CMPP, NIDA Notes Contributing Writer

This study:

  • Demonstrated that a novel compound alleviates inflammatory and neuropathic pain in mice without producing tolerance or signs of abuse liability.
  • Supports the hypothesis that compounds that act as positive allosteric modulators of the cannabinoid-type 1 receptor may offer effective and safe treatment for hard-to-treat types of pain.

NIDA-supported researchers report progress in developing medications that relieve chronic pain and do not, like opioids, lose effectiveness with continued use or carry risks for abuse and addiction. Dr. Andrea G. Hohmann, graduate student Richard A. Slivicki, and colleagues at Indiana University, Bloomington, successfully tested a compound that enhances the natural analgesic activity of the endocannabinoid system.

The endocannabinoid neurotransmission system is a component of the body’s natural mechanisms for controlling pain. Cannabinoid neurotransmitters (endocannabinoids) produce analgesic effects by stimulating cannabinoid-type 1 receptors (CB1Rs). Some drugs, notably marijuana’s ingredient tetrahydrocannabinol (THC), infiltrate this system to also activate CB1Rs. These drugs produce analgesia, but also produce unwanted side effects, including cognitive and mood changes and, in some people, addiction.

Figure 1. Orthosteric and Allosteric Binding to the Cannabinoid-Type 1 Receptor 1 (CB1R) Endocannabinoids and THC activate CB1R by binding to its orthosteric site (i.e., act as orthosteric ligands). GAT211 is a positive allosteric modulator that enhances the CB1R response to orthosteric activation by binding to the allosteric site. See full text description at end of article.

Dr. Hohmann and Mr. Slivicki propose that compounds that act as positive allosteric modulators (PAMs) of CB1Rs can strengthen endocannabinoids’ analgesic effects without producing unwanted THC-like side effects. PAMs are molecules that bind to receptors at sites (allosteric sites) that are distinct from the receptors’ typical activation sites (orthosteric sites) (see Figure 1). PAMs render receptors more responsive to activation by naturally occurring neurotransmitters; hence, CB1R PAMs may amplify the effects of endocannabinoid activation of CB1R, including analgesia. At the same time, because PAMs do not themselves activate receptors, CB1R PAMs may avoid the unwanted effects of cannabinoid pharmaceuticals, which bind to the orthosteric site and activate receptors throughout the brain.

The Indiana researchers investigated the analgesic and other effects of a CB1R PAM called GAT211, which was synthesized in the laboratory of Dr. Ganesh Thakur at Northeastern University. Mr. Slivicki, in experiments with mice, found that GAT211 suppressed pain responses in protocols that simulate human inflammatory pain and neuropathic pain:

  • Inflammatory pain: A single injection of GAT211 enabled animals to tolerate more mechanical pressure on a paw that had been exposed to an inflammation-causing chemical agent (complete Freud’s adjuvant).
  • Neuropathic pain: Daily injections of GAT211 enabled animals to tolerate more cold and mechanical pressure on a paw that had been exposed to a neuropathy-causing agent (paclitaxel) (see Figure 2). This analgesic effect was sustained with no loss of effectiveness over 19 days of treatment, equivalent to more than 2 years in the human life span.
Figure 2. GAT211 Can Suppress Neuropathic Pain in Mice Mice were exposed to the anticancer agent paclitaxel (PTX), which causes neuropathic hypersensitivity to mechanical pressure or cold compared with baseline (BL). GAT211 reduced the hypersensitivity, as shown by animals tolerating greater mechanical pressure on the paw before withdrawing it (left) and having shorter duration of hypersensitivity to cold (right). See full text description at end of article.

Moreover, GAT211 did not produce reward or dependence. Mice did not prefer a chamber that they associated with the receipt of GAT211 over one in which they had received vehicle solution. Nor did mice that had been treated with GAT211 for an extended period show signs of withdrawal when the researchers administered a compound that prevented CB1R activation. In contrast, mice treated with a THC-like cannabinoid drug exhibited profound physical withdrawal signs when exposed to the same CB1R blocker. In addition, when GAT211 was given together with other compounds that also increase activity in the endocannabinoid system, the combination treatment produced an enhanced therapeutic reduction of neuropathic pain.

Dr. Hohmann says there is an urgent need to identify effective analgesics that lack abuse potential, because chronic pain is a major factor contributing to the current epidemic in opioid addiction. She says, “I believe that CB1 allosteric modulators have the potential to change the face of pain management as we know it.”

The study was supported by NIH grants DA041229, DA009158, DA021696, and DA024628.

Text Description of Figure 1

The figure shows the proposed mechanism of action of endocannabinoids, THC, and GAT211. The figure shows part of a cell, with cannabinoid-type 1 (CB1) receptors indicated by the green molecules with several tube-like structures that are embedded into the membrane surrounding the cell. The top indicates the space outside the cell, the bottom the space inside the cell. On the left side of the figure, blue triangles indicated orthosteric ligands like endocannabinoids and THC, that bind to a specific region of the CB1 receptor, the orthosteric binding site. This binding initiates a signaling process within the cell, indicated by the black arrow. On the right side of the figure, some orthosteric ligand molecules are joined by positive allosteric modulators, indicated by the red hexagons. These modulators bind to a different region of the CB1 receptor, the allosteric binding site. Simultaneous binding of the orthosteric ligand to the orthosteric binding site and of the positive allosteric modulator to the allosteric binding site results in enhanced signaling processes in the cell, indicated by a thicker arrow.

Text Description of Figure 2

The figure shows two panels illustrating the activity of GAT211 in suppressing neuropathic pain in mice. The left panel shows on the horizontal x-axis the duration of the experiment in days. The vertical y-axis shows the pressure (in grams) that can be exerted on a mouse’s foot before the animal withdraws the foot. In untreated animals (i.e., at baseline [BL]), this pressure threshold is about 7 grams. If the animals are treated with paclitaxel (PTX) to induce neuropathic pain, the pressure threshold declines to about 3 grams. For mice that were treated with a saline solution for 8 days after PTX administration, the pressure threshold remained around 3 grams at 1, 4, and 8 days of treatment as shown by the purple curve. For animals that were treated with GAT211 for 8 days after PTX administration, the pressure threshold increased to about 5.5 grams on days 1 and 4 and to about 4.5 grams on day 8, as indicated by the green curve.

For the right panel, the horizontal x-axis again shows the duration of the experiment in days. The vertical y-axis shows the duration of hypersensitivity to cold in seconds. Untreated animals (BL) show hypersensitivity for about 3 seconds. PTX treatment increases the duration of hypersensitivity to cold to 5.5 to 6.5 seconds. For animals that were treated with saline solution for 8 days after PTX administration, hypersensitivity to cold remained elevated at about 6 seconds on days 1, 4, and 8, as indicated by the purple curve. For animals that were treated with GAT211 for 8 days after PTX administration, duration of hypersensitivity declined to about 4.5 seconds on day 1 and to about 3.5 seconds on days 4 and 8, as indicated by the green curve.

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