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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2679_Библиотеки_им_академика_М_И_Перельмана
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286 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
No Gain from Pain
Pain from a hot stove or an injury can be positive, as it can help prevent
more serious damage from occurring. Neuropathic pain, on the other
hand— which includes burning or aching pain —seemingly has no purpose. Analgesics that block only neuropathic pain are desirable but scarce.
Wanget al.recently identified a promising new drug candidate by screening for drugs that selectively block a type of calcium-activated adenylyl
cyclase that participates in neuropathic pain. NB001 is a novel compound,
which can block neuropathic pain in rodents, without apparent side
effects.
Adenylyl cyclase 1 has many characteristics of a good drug target for
neuropathic pain. Primarily adenylyl cyclase 1 is an activity-dependent
enzyme — expressed selectively in neurons — that is critical for painrelated neural plasticity which is believed to underlie this kind of pain.
The authors screened various chemical compounds for inhibition of cyclic
AMP production and the transcription factor CREB in human cells transfected with adenylyl cyclase 1. One of these compounds, named NB001,
was found to be most effective and also inhibited cyclic AMP production
in mouse brain slices and human neurons. NB001 prevented allodynia (a
condition in which an innocuous stimulus causes pain) in mice in which
certain nerves were ligated, and in mice with chronic inflammatory pain,
produced by an injection of an irritant into a paw. When NB001 was
injected directly into the anterior cingulate cortex (a brain region involved
in neuropathic pain generation), it also prevented allodynia, although to a
lesser extent, suggesting that NB001 acts on multiple sites in the body.
Just as important as the positive effects of NB001 on chronic pain are
the effects that it does not have. NB001 does not interfere with normal
nociception — the sensation that allows the animal to escape dangerous
heat. It does not affect neurotransmission of the critical hormone glutamate or the size of glutamate-induced currents. Tests of anxiety, motor
function, and fear all showed that NB001 had no effects on these endpoints, a good sign for the potential safety profile of this drug.
A clue as to how NB001 works can be gleaned from recent results that
show that it prevents the synapses in the dorsal horn of the spinal cord and
the anterior cingulate cortex from “learning” — a process triggered in
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neuropathic pain conditions. This effect may underlie its analgesic ability,
a conclusion consistent with the fact that it does not alter plasticity in the
hippocampus, a non-pain-related brain region. If the selective action of
NB001 on neuropathic pain, along with its lack of serious side effects,
also holds true in humans, it may prove to be a valuable treatment for pain.
Summary
Basic investigations of nociception and pain have provided us with a better understanding of the mechanisms of pain transmission, modulation,
and plasticity. However, the clinical treatment of chronic pain has not kept
pace with these discoveries. This failure to discover new and improved
treatments for chronic pain is at least in part due to the business model of
pharmaceutical industries and an oversensitive legal system. Many earlystage drug trials are terminated for reasons other than their scientific
value. Considering that the majority of cells in the body use most of the
common signaling proteins to form key signaling pathways, it is the next
great challenge for researchers to develop selective, yet effective, painkillers without dangerous side effects.
Keywords: Analgesia; LTP; AC1; chronic pain; NB001; inammatory
pain
Introduction
Revealing a novel mechanism and identifying a new target for pain are the
main focuses for most pain researchers and neuroscientists. The most
direct, and simple, idea for controlling pain is to identify selective proteins
that are preferentially involved in the pain process and discover/design
selective inhibitors for those proteins. However, the history of pain medicine research proves that this is easier said than done. Recent studies using
modern molecular and cellular neurobiology approaches found that pain
was not, in fact, transducted by a few signaling proteins. Even more bad
news is that many of the key proteins involved in pain processes, such as
chronic pain, also play key roles in physiological conditions. One good
example is NMDA NR2B receptor, while critical for cognitive functions,
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its activity also plays a critical role in chronic pain. This chapter will
review current drugs by focusing on their basic neurobiological mechanisms and introduce several new signaling proteins involved in chronic
pain, in order to explore potential future targets and treatments.
Distinguish physiological pain and pathological pain
Physiological pain is imperative for human survival. Physiological pain is
the first sign that tells an individual that something is wrong. The position,
quality, and duration of pain are crucial for a doctor to locate and diagnose
disease and also to appreciate the efficacy of treatment. Pain also serves
as a protective function. Pain, or the threat of pain, warns an individual to
avoid dangerous situations and to protect against self-harm. This protective function of pain is well demonstrated in patients with diabetes or
congenital insensitivity to pain. In diabetes cases, patients often lose pain
sensation due to a degeneration of peripheral nerve fibers. This degeneration prevents patients from feeling pain, often resulting in damage or
injury without awareness. Patients with congenital pain insensitivities
similarly struggle with injuring themselves inadvertently, and they often
die young as a result. Thus, understanding the physiological mechanism(s)
for pain, including how injury-producing stimuli transmit from the peripheral site to the CNS and how this nociceptive process could be modulated
by the CNS, is crucial for treatment of those patients with both acute and
chronic pain.
Injury most often leads to pain which lasts for an extended period of
time after the injury (persistent pain or chronic pain). Long-lasting pain,
or pathological pain, often leads to a wide range of dysfunctions in the
brain including anxiety, depression, and even suicide. While physiological
pain is likely to be conducted through precise physiological pain pathways— and under fine modulation of descending biphasic modulation—
pathological pain is more likely to be caused by activity-dependent
changes in a variety of brain regions. An understanding of the molecular
and cellular mechanisms of plastic changes in sensory-related brain areas
is essential to the development of clinical strategies aimed at alleviating
chronic pain. Because physiological pain is such an important function for
daily living, the next generation of drugs will need to selectively reduce
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chronic pain while keeping acute pain intact. Studies designed to treat
chronic pain need to consider how to maintain physiological pain while
reducing or abolishing pain-induced unpleasantness or discomfort
selectively.
Inhibiting pain transmission as drug action
mechanism: Traditional approach to develop
analgesic
Based on what we have discussed so far, it is possible to think of different
methods for controlling pain. Most of the clinically effective drugs can be
explained by using the animal model of chronic pain. It must be noted that
there are possible differences between the species, and the side effects of
drugs on humans cannot be predicted with animal models. More importantly, the human body is made of many common signaling proteins from
the testis to the central neurons. It may be unavoidable that even the most
effective pain drugs come with significant side effects. Based on basic
mechanisms, this chapter will discuss pain drugs in the following order:
1. drugs that targeted peripheral transmission and sensitization,
2. drugs that affect sensory transmission in the spinal cord or supraspinal
structures,
3. drugs that act to activate descending modulation,
4. drugs that act to block pain plasticity.
Table 1 summarizes most of the current drugs or obvious drug candidates for the treatment of chronic pain.
Peripheral inhibition
For targeting peripheral transmission, there are several drugs available for
topical use. The first is lidocaine. Lidocaine is an amide-type local anesthetic that produces its effect by blocking voltage-dependent sodium
channels. It reduced excitability in peripheral nociceptors. The second
drug is capsaicin. Capsaicin mediates its effect by activating the transient
receptor potential type 1 (TRPV1) receptor. TRPV1 is preferentially
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Table 1. Pain medicines currently used and their synaptic mechanisms
Classes Clinical drugs Types of drugs Major synaptic
mechanisms
Type I SNX-111 N-type calcium
channel blocker
LY293558 AMPA/kainate
receptor antagonist
Type II Ketamine, CPP NMDA receptor
antagonist
Type III Clonidine
Neostigmine Cholinesterase
Morphine and
other similar
drugs
Celebrex Cyclooxygenase
Type IV GABApentin Enhancing inhibitory
α2 adrenergic
receptor agonist
inhibitor
µ-opioid receptor
agonist
subtype 2 inhibitor
Inhibiting transmitter
release
Inhibiting postsynaptic
excitatory currents
Blocking glutamatergic
synaptic plasticity
and transmission
Inhibiting sensory
synapses
Inhibiting sensory
synapses
Inhibiting sensory
synapses
Inhibiting sensory
synapses
transmission
Clinical pain
conditions
Cancer pain
Hyperalgesia and/or
allodynia
Neuropathic pain,
post-operative pain
Cancer pain,
neuropathic pain,
postoperative pain
Cancer pain,
postoperative pain
Cancer pain,
postoperative pain
Cancer pain,
postoperative pain
Neuropathic pain
expressed in nociceptive primary afferent neurons [1,2]. It likely produced
analgesic effects by altering the sensitivity of peripheral sensory fibers.
One lead drug target for pain is a novel receptor antagonist for TRPV1
receptors. Based on its selectively involvement in nociceptive transmission, it is likely that it may contribute to injury-related hyperalgesia but
not allodynia. All these drugs are less, or not, effective in treating centrally
related chronic pain. Furthermore, recent studies indicate that TRPV1
receptors are also distributed in other parts of the brain such as the cortex
and hippocampus — areas that are also important for memory and other
key brain functions. The TRPV1 receptor is found to play a key role in
body temperature maintenance and the TRPV1 antagonist is reported to
produce dramatic changes in body temperature. In the ACC, a selective
TRPV1 antagonist failed to produce any inhibition of chronic pain-related
LTP (see Figure 1), suggesting that it is unlikely to affect cortical sanitization in chronic pain.
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(a) (b)
(c) (d)
Figure 1. SB366791 cannot block the induction of LTP in the adult mice ACC. (a)
Grouped data from 6 slices of 6 mice for SB366791 (20μM), showing the normal induction of LTP in the superficial layer. (b) Summarized data in the deep layer (n = 6 slices/6
mice). Sample fEPSP recordings taken at the times indicated by the corresponding numbers are shown at the top of each plot. Arrows in (a and b)show the starting point of TBS
application. Horizontal bars denote the period of drug delivery. Calibration: 100 μV,
10ms. Error bars represent SEM. (c, d)Spatial analysis of the effect of SB366791 on LTP
distribution in the ACC. Shown are polygonal graphs of the channels that were activated
(blue, c) and that exhibited LTP (red, d) when TBS was delivered in the presence of
SB366791 (n = 6 slices/6 mice). Vertical lines denote the specific layers in the ACC slice.
SB366791 has no effect on the LTP distribution map in the ACC (adapted from Liu and
Zhuo [66]).
Opioids
Drugs targeting sensory synaptic transmission and modulation are more
well-known, such as opioids, cannabinoids, calcium channel blockers,
Cox-2 inhibitors, as well as anticonvulsants, and antidepressants. Opioid
analgesics include morphine and other opioid agonists. These drugs are
used to treat moderate to severe pain. Morphine and other opioid drugs
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produce analgesia by binding to opioid receptors expressed in the central
nervous system, including the cortex, brainstem, spinal cord, and peripheral tissues. Activation of these receptors affects both excitatory and
inhibitory transmission in the central synapses. There are three major
subtypes of opioid receptors: the mu-, kappa-, and delta-opioid receptors.
Most of the opioid drugs act by activation of µ receptor, such as morphine,
hydromorphone, oxycodone, fentanyl, and meperidine. Activation of opioid receptors triggers Gi/Go protein-coupled signaling pathways. At the
synaptic level, it will inhibit voltage-gated calcium channels that are
required for neurotransmitter release presynaptically and induce an
inwardly rectifying potassium conductance postsynaptically. In addition,
it may also trigger receptor internalization which explains the relatively
short analgesic effect of opioids. It has also been reported that opioids
affect inhibitory transmission in the spinal cord, thus not selective for
excitatory transmission. Since injury-related pain plasticity is NMDA
receptor-dependent, the application of opioids is unlikely to block painrelated plasticity. A recent study showed that a brief application of a high
opioid dose can reverse injury-related LTP in spinal cord C fiber synapses,
effectively erasing a spinal memory trace of pain.
The action of opioids likely varies at the different levels of the CNS.
Peripheral effects have been reported, although the major analgesic effect
is likely from its action in the CNS. In the cortex, opioids are highly
expressed and inhibited excitatory transmission in the pain-related cortical
areas, such as the ACC. Its cortical action is likely reducing pain perception by affecting excitatory synapses. In addition, the PAG and the RVM
are important for opioid analgesia. Opioids activate descending inhibitory
pathways to the spinal cord which are mediated by multiple neurotransmitters including serotonin, noradrenaline, acetylcholine, and neuropeptides in the dorsal horn. At the spinal cord level, mu opioids act
presynaptically to inhibit neurotransmitter release and postsynaptically to
inhibit dorsal horn neurons firing to peripheral stimulation.
In addition to the relatively rapid loss of analgesic effects over time,
opioid usage for the treatment of chronic pain is also limited by its very
powerful side effects. Side effects can include sedation, mental clouding
or confusion, respiratory depression, nausea, vomiting, constipation, pruritus (itch), and urinary retention.
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Cannabinoids
Cannabinoids are compounds that activate the cannabinoid receptors. They
include endocannabinoids (produced endogenously in the body), phytocannabinoids (produced by Cannabis plants), and cannabimimetics
(produced synthetically and by various plant species). One of the most
notable cannabinoids is ∆9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis. However, there are numerous other cannabinoids with various effects. There are two major types of cannabinoid
receptors: CB1 and CB2. CB1 receptors are found primarily in the brain,
including the basal ganglia, limbic system, cerebellum, and reproductive
systems. CB1 receptors are mainly responsible for the euphoric and anticonvulsive effects. CB2 receptors are predominantly found in the immune
system and maybe be responsible for the possible anti-inflammatory effects.
Due to its central distribution, activation of CB1 receptors has been
shown to inhibit nociceptive responses in central sensory synapses, which
suggests that CB1 receptor agonists may be beneficial for controlling pain.
However, the effect of CB1 receptor activation is not selective. It also
affects synaptic regulation and learning-related plasticity (LTP and LTD)
in the cortex, hippocampus, and cerebellum [3]. This explains the
side effects of these drugs on cognitive and emotional functions.
Endocannabinoids are known to serve as intercellular ‘diffusible messengers’ in key brain regions, including the hippocampus. They also contribute to synaptic LTP that is known to be critical for memory. Although
some animal behavioral studies suggest that CB2 agonists may be analgesic for chronic pain, the basic mechanisms for such analgesics are still
lacking. It is worthwhile to point out that conclusions from pure animal
models of pain often fail to translate in human patients.
Calcium channel blockers
Voltage-gated calcium channels, especially N-type calcium channels, are
important for sensory synaptic transmission. The calcium channel blocker
ziconotide is a synthetic version of the naturally occurring omega-conotoxin MVIIA and inhibits voltage-gated N-type calcium channels. N-type
calcium channels are widely distributed in the nervous system and are
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required for normal physiological synapse functions. They are also widely
distributed in the postsynaptic structures of neurons. Due to the negative
side effects ziconotide has on the CNS (nausea, vomiting, and dizziness),
it is limited in intrathecal applications in pain patients.
Sodium channel blockers
Inhibition of local sensory sodium channels is thought to be the ideal and
safe way to reduce chronic pain, especially neuropathic pain. Different
chemical inhibitors have been developed to target certain sodium channel
subtypes, however the administration of sodium channel blockers is also
limited by central side effects. Some of the similar subtype channels are also
expressed in the heart, as well as other key central brain areas. The ineffectiveness of inhibitors is also reported in certain forms of chronic pain.
Cox-2 inhibitor
Mild to moderate pain is often treated with non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are effective in reducing the hyperalgesia
associated with tissue injury and inflammation but are less effective for
treating neuropathic pain. NSAID drugs produce their effects by inhibiting cyclooxygenase (COX). COX is the rate-limiting enzyme in the production of prostaglandins, which are derived from C-20 unsaturated fatty
acids, mainly arachidonic acid. Arachidonic acid is formed from membrane phospholipids by activation of phospholipase A2. COX converts
arachidonic acid to prostaglandin H2 (PGH2), which is subsequently catalyzed to PGD2, PGE2, PF2a, and PGI2 by specific synthases for the different prostaglandins. In addition, COX catalyzes the generation of
thromboxanes, leukotrienes, and lipoxins. Together, these substances are
referred to as eicosanoids. The prostaglandins mediate their action by
binding to specific membrane receptors (DP, EP, FP, and IP) that are
G-protein-coupled receptors. Tissue injury and inflammation result in
prostanoid production at the site of tissue injury and inflammation. Once
released at the site of injury, prostaglandins act on prostaglandin receptors
on primary afferent terminals to produce sensitization and behavioral
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hyperalgesia. In addition, tissue injury and inflammation are associated
with elevated prostaglandin levels and induction of COX-2 at the spinal
cord level. Thus, prostaglandins may not only produce sensitization in the
periphery but also contribute to sensitization mechanisms at the spinal
cord level. The major benefit of COX-2, over Cox inhibitors, is the
reduced gastrointestinal side effects. It is unclear whether Cox-2 inhibitors are any better than non-selective Cox inhibitors in terms of the neurobiological effects, however, the recent discovery of negative
cardiovascular side effects of COX-2 has led to a diminished use of Cox-2
drugs for pain control.
Anticonvulsants
The anticonvulsants represent a group of compounds with diverse chemical structures and different mechanisms of action. Several anticonvulsants
are potent blockers of voltage-gated sodium channels, including carbamazepine, phenytoin, lamotrigine, topiramate, and felbamate. Gabapentin
is the only anticonvulsant approved for the treatment of neuropathic pain
(postherpetic neuralgia), and its activity is thought to be a result of the
inhibition of voltage-sensitive calcium channels and modulation of the
GABA system. In a recent study, it was found that gabapentin reduced
excitatory synaptic transmission in the ACC while LTP was not blocked
[24] (Figure 2). Pregabalin is a similar compound to gabapentin.
Antidepressants
Tricyclic antidepressant drugs (TCAs), such as amitriptyline, may be
effective in treating painful conditions, such as neuropathic pain. There
are different mechanisms that may contribute to the pain-relieving effects
of TCAs, such as the reuptake inhibition of noradrenaline and serotonin,
blockade of Na ion channels, and the inhibition of NMDA receptors.
Changes in NE and 5-HT levels may affect descending pain modulatory
systems, especially descending inhibitory systems. The exact mechanisms
at the cellular and molecular levels remain to be investigated, but this family of drugs will affect physiological pain.
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