Note from the Editor (10/8/21): One of the writers of this 2006 study, David Julius, is a co-recipient of the Nobel Prize in Physiology or Medicine in 2021 for discoveries into how the human body feels temperature and touch.
The pain was throbbing, itching, aching, stabbing, stinging, pounding, and piercing.
Pain has a variety of unpleasant flavors to it. But all pain has one thing in common: the desire to be free of it.
However, the most often used analgesics today are essentially centuries-old folk remedies: morphine and other opiates are derived from the opium plant, and aspirin is derived from willow bark.
Although these treatments can provide relief, they all have their own set of limitations. Aspirin and other nonsteroidal anti-inflammatory medicines (NSAIDs) like ibuprofen are unable to relieve the most severe types of pain.
Even the most powerful medicines, opiates, do not work for everyone.
Furthermore, they can have substantial adverse effects, and patients often develop tolerance of them, necessitating higher doses to achieve any relief.
Neurobiologists have learned a lot about the cellular circuits and specific molecules that transport pain signals in the last 20 years.
This knowledge is currently being used to develop new ways for improved pain management with fewer side effects.
Indeed, there are now more approaches under investigation than we have space to discuss.
FIRE-RELATED PARTICLES
René Descartes, a 17th-century French philosopher, devised a theory to explain how individuals perceive pain.
A pinch, a wallop, or a poke, in his opinion, essentially yanked on a neural rope, which sounded a pain alarm bell in the brain.
Consider the case of a foot that has been burned.
Descartes reasoned that “fast moving particles of fire” would cause a disturbance that “passes down the nerve filament until it reaches the brain.”
Descartes was not far behind. The pain usually starts in the periphery, such as in the skin, an internal organ, or anywhere else outside the central nervous system (CNS), which includes the brain and spinal cord.
Stubbing a toe or leaning on a hot stove stimulates nociceptors, which are neurons (nerve cells) that respond to painful stimuli like excessive temperature or mechanical pressure, as well as chemicals produced in response to injury or inflammation.
Nociceptors have two arms: one that detects sensations and expands out to the periphery, innervating small patches of tissue, and the other that reaches into the spinal cord [see box below].
The cell body of the neuron, which is located outside the spine, is sandwiched between the two.
When specialized detector molecules on the peripheral branch come into contact with a noxious agent in the skin or an organ, they send an impulse up the line, up the central branch, and into the dorsal horn of the spinal cord.
The nociceptor then releases neurotransmitters, which activate neurons in the dorsal horn, causing them to send the alarm message to the brain.
Although nociceptors are commonly referred to as pain-sensing neurons, they just signal the existence of potentially hazardous stimuli; the brain is the one who interprets the signal as painful and causes us to say “ouch.”
Not all pain is alarming. The acute type, which occurs after a minor tissue injury like a sprain or abrasion, is protective: it encourages an organism to avoid additional injury. This type is usually only transient and fades away over time.
The pain that patients—and doctors—worry about does not go away and is tough to cure.
The issue emerges in many cases because of the damage or inflammation that causes the discomfort lingers.
Arthritis pain is caused by chronic inflammation, and the misery that can accompany aggressive malignancy is caused in part by tissue injury and inflammation.
In some circumstances, prolonged pain is neuropathic, meaning it is caused by damage to nerve cells.
Multiple sclerosis, a stroke, or a spinal cord injury, for example, can destroy neurons in the CNS, causing it to develop.
It could also be caused by damage to peripheral neurons.
Neuropathic pain affects amputees who experience aching in a limb that is no longer there (phantom limb pain) and others who have to burn in their skin for years after a herpes infection has passed (postherpetic neuralgia).
When this type of pain persists, it is not an indication of an ongoing injury or another disease; it is a nervous system disorder that necessitates the attention of a pain specialist.
PAIN THAT DOESN’T END
Abnormal sensitivity to stimuli is a common denominator among persons who suffer from difficult-to-manage pain.
Hyperalgesia (exaggerated response to traditionally unpleasant inputs) and allodynia are two types of sensitivity (pain in response to normally innocuous inputs).
Even the slightest pressure of garments against one’s skin or bending a joint can be excruciating for those suffering from allodynia.
Biologists now know that molecular or structural changes in nerve cells cause increased sensitivity or sensitization.
Molecules that increase inflammation in the periphery, for example, may lead nociceptors that detect noxious stimuli to become too receptive to those inputs.
Inflammatory chemicals can even trigger nociceptors to start sending signals even when there is no external stimulus.
Sensitization can also be caused by CNS alterations that cause pain-transmission channels to become hyperactive.
Increased numbers of receptors that respond to neurotransmitters generated by nociceptors, as well as rewiring of connections and the loss of nerve cells that typically block pain signaling, are among the alterations that can last a long time.
The syndrome is known as central sensitization when the CNS is implicated.
Regardless of whatever precise processes are to blame, it turns out that chronic pain can cause sensitization, which can increase and prolong the discomfort.
As a result, several researchers are looking for new analgesics to reduce hyperalgesia and allodynia.
Meanwhile, patients must understand that chronic pain should not be tolerated passively; it necessitates vigorous therapy to avoid additional sensitization.
START FROM THE VERY BEGINNING
Much of the effort in the hunt for new analgesics has been focused on the periphery, which is where most painful signals originate.
Some of the specific chemicals that nociceptors use to detect noxious stimuli are only found in nociceptors and are rarely found elsewhere in the body.
Blocking these molecules would theoretically turn off pain signaling without interfering with other physiological processes and, as a result, without creating undesirable side effects.
Aspirin and other NSAIDs, which are among today’s most common treatments, mostly work on the periphery.
When tissue is wounded, several cells in the area release substances called prostaglandins, which act on nociceptors’ pain-sensing branches, reducing their activation threshold.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) block the function of cyclooxygenases, a class of enzymes that cells utilize to make pain-inducing prostaglandins.
These over-the-counter medications help with minor aches and pains.
However, they also block prostaglandin production in other parts of the body, resulting in stomach pain, diarrhea, and ulcers.
These issues may preclude long-term usage of the medications and limit the doses that can be given.
Pharmaceutical firms created a series of medications that target the enzyme cyclooxygenase-2 to alleviate gastrointestinal side effects (COX-2).
Because COX-2 isn’t generally active in the stomach or intestine, inhibiting its activity shouldn’t produce the same problems as standard NSAIDs.
It’s still unclear whether they’re gentler on the stomach.
In the meantime, the drugs have their issues. Rofecoxib (Vioxx), a COX-2 inhibitor used to treat arthritic pain, was taken off the market after it was discovered to increase the risk of heart attack and stroke.
Other COX-2 inhibitors are also being studied to see if they have any negative side effects.
SEND IN THE SALSA PERFORMERS
The discovery of targets that are nearly exclusively found on nociceptors opened the door to the development of pain-relieving medicines.
The capsaicin receptor is one of the most attractive. Many nociceptors include this ion channel, which response to capsaicin, the pungent element in chili peppers, as well as distressing heat and protons (hydrogen ions that make things acidic); protons are notably numerous in inflamed tissue.
The channel allows sodium and calcium ions to flood into the nociceptor in the presence of these chemicals or temperatures above 43 degrees Celsius, activating it to generate a signal that translates into the burning sensation caused by heat, inflammation, or spicy food.
As a result, substances that suppress capsaicin receptors should reduce inflammatory pain.
Indeed, such “antagonists” have been shown to ease the excruciating pain caused by the acidic environment around tumors that have metastasized to and damaged bone tissue in laboratory animals.
Capsaicin receptor antagonists are currently being developed by several pharmaceutical companies.
The number of ways to manipulate the receptor does not end there.
In certain cases, purposefully stimulating capsaicin receptors might relieve pain.
Capsaicin-containing topical lotions are being given to alleviate the itching, prickling, and stinging sensations that can follow postoperative wound healing or nerve deficits caused by HIV infection, herpes, or diabetes.
The exact mechanism of action of the ointments is unknown, while little doses over time may make the receptor less sensitive to normal stimuli or cause neurotransmitter depletion in nociceptors.
TURN OFF ALL OTHER CHANNELS
A different type of chemical discovered on nociceptors’ peripheral terminals is also receiving attention as a potential therapeutic target.
Sodium channels are found in all neurons, and they open in response to voltage changes across the nerve cell membrane, creating the impulses that transport messages from one neuron to the next.
Local anesthetics that temporarily inactivate voltage-gated sodium channels are currently used to alleviate a range of ailments, including those associated with dental visits.
The concern is that such anesthetics must be given directly to the source of pain; otherwise, inhibiting sodium channels throughout the nervous system could be lethal.
However, pain-sensing neurons have a subclass of voltage-gated sodium channels called TTX-resistant sodium channels that are not found in the CNS.
As a result, researchers expect that medications that can block this subclass can be given systemically (all over the body) without causing harm.
Furthermore, investigations suggest that such medicines could effectively decrease the excessive excitability of injured peripheral neurons, alleviating some neuropathic pain.
Unfortunately, the pharmaceutical industry has yet to produce selective inhibitors for these channels, in part because they are similar to TTX-sensitive sodium channels, which are found throughout the nervous system.
However, a novel approach known as RNA interference may be able to selectively eliminate the channels.
The procedure involves injecting tiny molecules known as small AMADEO BACHAR interfering RNAs into an organism (siRNAs).
By causing the breakdown of the molecules (messenger RNAs) that control the protein’s synthesis, these siRNAs prohibit the development of an undesired protein.
Although the approach is being tested in people for some retinal diseases, converting RNA interference into a pharmaceutical pain treatment will be difficult.
A virus will almost certainly be required to deliver siRNA, as is the case with gene therapy, and this element has prompted safety concerns.
It will take time to see if the strategy can be used as a pain treatment, but it is an intriguing option.
Assume that drug companies produce a so-called “magic bullet” analgesic: a substance that blocks the action of one of the pain-transducing molecules on nociceptors selectively and effectively.
Is there a chance that this strategy could help with intractable pain? Maybe not, because cutting down just one pain pathway entrance might not be enough.
Consider a drug that disables the receptor for bradykinin, a tiny protein or peptide generated in the peripheral nervous system during inflammation.
Bradykinin activates nociceptors quite strongly, and an antagonist that inhibits its receptors would certainly prevent nociceptors from being activated.
It would not, however, prevent the neurons from identifying and responding to other pain-inducing chemicals produced by injury or inflammation, such as protons, prostaglandins, and a protein known as a nerve growth factor.
Similarly, inhibiting solely the capsaicin receptors may not alleviate all proton-mediated pain, because protons can activate a distinct population of detectors on nociceptors called ASICs (acid-sensing ion channels) in certain conditions.
KEY IN ON THE CORD
A mixture of inhibitory compounds that target numerous pain systems would be one approach to get around this redundancy problem.
Another strategy would target molecules that act more centrally, preventing all nociceptors from transmitting pain signals to spinal cord neurons, regardless of what stimuli first stimulated them.
This is how opiates like morphine and other opiates work.
They connect to opioid receptors on nociceptor endings that stretch into the spinal cord.
Opioids limit neurotransmitter release by activating these receptors, preventing pain signals from reaching spinal cord neurons.
They also reduce the ability of dorsal horn neurons to respond to pain signals.
Because these medications act on the spinal cord, they should theoretically be able to treat any form of pain, however, they are most effective against inflammation-related pain.
Opioid receptors can be found on neurons all over the body, including the brain and the gastrointestinal system.
Because of its widespread use, morphine and its cousins can cause a wide range of negative side effects, including severe constipation and respiratory arrest.
These issues may limit the amount of medication that a patient can safely take or that a doctor will prescribe.
Many doctors are also hesitant to administer opiates for fear of their patients becoming hooked. Addiction is uncommon in those who simply use opioids to relieve pain.
Opioids are frequently given directly into the fluid-filled region around the spinal cord, in part to avoid some of the negative effects (intrathecally).
Injections (for postoperative pain) or an indwelling pump can also be used to give the medications (for chronic pain).
Opioid substitutions are also available. Medicines that block calcium channels can inhibit neurotransmitters from being released from nociceptor terminals in the spinal cord.
Anticonvulsant gabapentin (Neurontin) is thought to reduce pain by interacting with a particular subunit of certain calcium channels.
In addition, ziconotide (Prialt), a relatively new medication derived from the venom of a Pacific Ocean cone snail, inhibits a distinct type of calcium channel known as the N-type.
N-type calcium channels, like opioid receptors, are found throughout the neurological system.
Blood pressure would drop dramatically if ziconotide was given systemically. As a result, the drug is given intravenously.
Despite the toxin’s ability to block pain, its action within the CNS can cause unpleasant side effects such as dizziness, nausea, headache, and confusion.
As a result, ziconotide is typically prescribed to patients with advanced cancer who have exhausted all other options.
Drugs that act on cannabinoid receptors—the receptors that underlie the effects of marijuana—have recently advanced through clinical studies.
These compounds appear to relieve pain in a variety of ways, including by interfering with nociceptors’ signal transmission and lowering the activity of inflammatory cells.
BATTEN DOWN THE HATCHES
Some researchers are focusing their efforts on blocking spinal neurons from responding to neurotransmitters generated by nociceptors, particularly glutamate, the major pain messenger.
Glutamate stimulates several receptors in the spinal cord’s dorsal horn. The NMDA class is involved in central sensitization, making it an obvious target for novel analgesics.
NMDA receptors are found on every cell in the body.
As a result, blocking all types at the same time would have disastrous consequences, including memory loss, convulsions, and paralysis.
To prevent such reactions, researchers are aiming to stifle the receptor by targeting dorsal horn variants.
Animal studies have shown that compounds that bind to a version containing the NR2B subunit had positive results.
Mice given an NR2B inhibitor directly into the spinal fluid, for example, were less responsive to pain than untreated mice.
In mice with peripheral nerve damage, the medication also reversed allodynia.
Peptide neurotransmitters, such as substance P and calcitonin gene-related peptide, are also released by nociceptors (CGRP).
Because these peptides activate pain-transmission neurons in the spinal cord by interacting with specific receptors, medications that block those interactions should be beneficial.
Unfortunately, selective inhibition of the neurokinin-1, or NK-1, receptor, which is exploited by substance P, has failed in human studies for pain, possibly because inhibiting that receptor alone is insufficient.
Although the pharmaceutical industry is developing antagonists that aim to relieve the suffering of migraines by interfering with the release of CGRP onto blood vessels on the surface of the brain, it is unknown whether quieting CGRP activity in the spinal cord will shut down pain.
ARE YOU GOING TO KILL THE MESSENGER?
If all other methods of pain modulation fail, one option is to kill the messenger.
Cutting nociceptive nerves, on the other hand, almost always backfires because, as we’ve seen, nerve injury can lead to the beginning of even more obstinate, long-lasting pain.
Cordotomy (severing channels in the spinal cord that transmit information to the brain) was historically widespread, but it is now reserved for terminal cancer patients who have failed to respond to all other pain treatments.
The issue with this last treatment is that the surgeon is unable to cut the “pain” routes selectively.
A molecular therapy that eliminates a subset of the spinal cord neurons receiving information from nociceptors is one prospective approach that is gaining traction due to its efficacy in animals.
Saporin, a toxin, is combined with substance P in this cell-killing therapy.
The conjugate’s substance P attaches to NK-1 receptors, causing the entire complex to be internalized, after which the saporin is released to kill the neuron.
Researchers expect that negative effects will be minimal because the compound can only penetrate cells that have an NK-1 receptor.
Ablation of neurons in the spinal cord, on the other hand, should be regarded as a last resort because neurons in the CNS do not regenerate, therefore the changes that ensue will be permanent, for better or worse.
In the peripheral nervous system, where cut fibers can regenerate, the same permanence does not apply. High dosages of capsaicin, for example, would ideally stop the pain while allowing the signal-detecting branches of nociceptors to grow back, restoring normal pain detection to the patch of tissue innervated previously.
Neuronal targeting may not be the only option for pain relief. According to research, when peripheral nerves are damaged, glia, the cells that nourish neurons in the CNS, go into action.
Glia migrates to the damaged nerves in the dorsal horn.
The glia then produces a slew of chemicals, which stimulate nociceptor terminals to release neurotransmitters in the spinal cord, thus prolonging the pain signal.
Some of these substances, like growth factors and cytokines, cause excessive excitability in dorsal horn neurons, and medications that prevent this hyperactivity should assist to reduce excessive sensitivity.
Several organizations are attempting to uncover the chemicals that recruit and activate glia when neurons are injured, as well as techniques to suppress them.
Prostaglandins are one of the main compounds released by activated glia in the spinal cord, which is interesting.
They inhibit glycine receptors on dorsal horn neurons, which increases pain. These neurons are generally silenced by glycine, an inhibitory neurotransmitter.
NSAIDs may thus function by suppressing COX enzymes in glia as well as interfering with prostaglandin production in the periphery (as previously thought).
In that instance, delivering COX inhibitors directly into the spinal fluid could reduce the negative effects of systemic administration. A drug that increased glycine receptor activation could be able to reduce pain transmission to the brain.
A PERCEPTIONAL CONTROVERSY
We’ve covered a selection of experimental pain-relieving techniques in this article, all of which have shown promise in animal experiments.
Those that elicit the most thrill maintain normal feeling while reducing the heightened sensitivity associated with difficult-to-treat inflammatory and neuropathic symptoms, as well as having a manageable side-effect profile.
Will these treatments, on the other hand, be beneficial to patients? Will they be effective in treating all types of pain? These are still unresolved questions.
The use of behavioral, nondrug therapy for persistent pain, especially that associated with illnesses like fibromyalgia and irritable bowel syndrome, for which no definitive organic etiology has been found, is one method that needs more investigation.
Researchers from McGill University discovered that hypnosis might change brain activity as well as a person’s sense of pain around a decade ago.
Volunteers were hypnotized and told that the hot water bath in which their hands had been plunged was either more or less uncomfortable than it was.
The researchers discovered that the somatosensory cortex, which response to the size of physical stimulation, was similarly active in both cases using positron-emission tomography scanning to monitor brain activity.
However, when subjects believed the stimulus was more unpleasant, a second brain region, the cingulate cortex, was more active, implying that hypnosis altered their perception of feelings.
Investigators may be able to develop better cognitive therapies for modifying pain perception if they learn more about how the brain adjusts the pain experience.
Emily Dickinson was a poet who frequently reflected on her suffering. She wrote in one piece, “Pain has a blank element to it; it can’t remember when it started, or if there was ever a day when it wasn’t.”
It doesn’t have a future other than that of itself.
We can only hope that continuing study into the processes of pain-sensing will lead to safe, effective medicines that will change the future of pain, allowing it to return to its former state.
About authors:
Allan Irwin Basbaum is professor and chair of the Department of Anatomy at the University of California, San Francisco. He is a Fellow of the American Academy of Arts and Sciences.
David Julius is professor and chair of the Department of Physiology at University of California, San Francisco and holds the Morris Herzstein Chair in Molecular Biology and Medicine. He is a member of the National Academy of Sciences and the American Academy of Arts and Science and has won numerous honors and awards, including the 2021 Nobel Prize in Physiology or Medicine.
