How do patches containing capsaicin relieve pain?

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How do patches containing capsaicin relieve pain?

In: Biology

We know capsaicin activates TRPV1 receptors on nociceptive (pain) neurons. Which means, it induces pain. But at the same time, it has pretty well established analgesic (pain reducing) effects. Seems paradoxical doesn’t it? Well I will copy paste a few excerpts from a paper to explain the proposed evidence-based mechanisms:

> The effects of capsaicin on nociception are not limited to its ability to produce pain. In fact, high or repeated doses of capsaicin induces an initial pain sensation that is followed by analgesia [76]. This loss of sensitivity to painful stimuli was noticed in response to not only thermal, but also mechanical and chemical noxious stimuli.

> After exposure to a high or repeated dose of capsaicin, the TRPV1 receptors begin a refractory state commonly termed as **desensitization** that leads to inhibition of receptor function

> Capsaicin activates TRPV1, which **inhibits Piezo proteins** , a
family of mammalian cation-selective ion channels that respond to mechanical stretch [86]. Inhibition of Piezo proteins occurs due to calcium-dependent activation of phospholipase Cδ (PLCδ), which depletes phosphoinositides. In fact, injection of phosphoinositides in the cytosol by excised inside-out patch clamp reduces rundown inward current of Piezo channels and reverts inactivation [86]. Therefore, the depletion of these phosphoinositides correlates with inhibition of mechanical-stimulation of Piezo channels through inhibition of inward current [86]. This work uncovers, at least in part, how local capsaicin produces mechanical analgesia.

> Capsaicin-induced analgesia is also related to **degeneration of sensory fibers [**87–90]. The mechanisms through which capsaicin causes cell death are not completely understood. Recent studies indicate that one of the most likely mechanisms is apoptosis via caspase activation. An
in vitro study demonstrated capsaicin induces DNA fragmentation and reduction of the nucleus in a caspase-dependent manner secondary to cell death of sensory neurons. In addition, the cell death process triggered by capsaicin via TRPV1 is directly related to mitochondrial permeability
transition [91]. On the other hand, capsaicin can promote cell death by apoptosis-independent mechanisms such as cell swelling and bleb formation in the membrane

> In addition to peripheral changes, **supraspinal mechanisms** also modulate capsaicin-induced analgesia. The subdermal injection of capsaicin significantly reduces the jaw-opening reflex and
increases the withdrawal threshold to mechanical stimulation in anesthetized rat, and both effects are prevented by microinjection of dopaminergic or opioid antagonist into the nucleus accumbens.
The tonic GABAergic inhibition of neurotransmission in the rostral ventromedial medulla (RVM) is also involved in capsaicin-induced analgesia modulation.

> Capsaicin also induces analgesia when administered centrally in varied foci. For instance, the intrathecal injection of capsaicin or RTX produces long-term regional analgesia with **substance P depletion **[101–103].

And to summarize:

> Supraspinal mechanisms of capsaicin-induced analgesia. Subdermal injection of capsaicin produces analgesia by modulating dopaminergic pathway in the NAc (1) [96], opioid pathway in the hippocampus (2) [98], and GABAergic activity in the RVM (3) [96,97]. In addition, vlPAG
injection of capsaicin activates endocannabinoid pathway (4) [99], and dPAG by modulating glutamate signaling pathway (5) [100]. Intrathecal injection of capsaicin depletes substance P and also produces
analgesia (6) [101–103]. DRG: dorsal root ganglion; NAc: nucleus accumbens; Hyp: hippocampus; RVM: rostral ventromedial medulla; PAG: periaqueductal gray; vlPAG: ventrolateral periaqueductal gray; dPAG: dorsal periaqueductal gray

And to summarize, in ELI5:

**Capsaicin acts as an analgesic by modulating both central (brain and spinal cord) and peripheral (body) pathways. These include dopaminergic, opioid, GABAergic, glutaminergic, and endocannabinoid pathways in the brain and spinal column. And desensitization of pain receptors in peripheral neurons, killing of pain neurons, depletion of substance P, inhibition of piezo proteins, etc. Together these explain why capsaicin alleviates heat, mechanical, and inflammatory pain. Of course, keep in mind, not all of these mechanisms are at work in a capsaicin patch, likely only local peripheral (near skin it was applied) mechanisms such as desensitization and piezo inhibition. Also some of these mechanisms were shown with doses that may not be used in patches. Capsaicin also has countless other known effects such as those on blood pressure. So it involves a complicated and convoluted set of mechanisms that we’re still studying.**

Here is the paper I used in case you’re interested:

https://www.mdpi.com/1420-3049/21/7/844/pdf