Recent research has implicated potassium channel function in chronic pain. For those interested in the science, here are nine highly technical articles from PubMed that explore this idea:
Potassium (K+) channels are crucial determinants of neuronal activity throughout the nervous system. Opening of these channels facilitates a hyperpolarizing K+ efflux across the plasma membrane that counteracts inward ion conductance and therefore limits neuronal excitability.
Accumulating research has highlighted a prominent involvement of K+ channels in nociceptive processing, particularly in determining peripheral hyperexcitability. We review salient findings from expression, pharmacological, and genetic studies that have untangled a hitherto undervalued contribution of K+ channels in maladaptive pain signaling. These emerging data provide a framework to explain enigmatic pain syndromes and to design novel pharmacological treatments for these debilitating states.
Four families of potassium channels with different structures, functional characteristics and pharmacological sensitivity, are distinguished in neurons:
- voltage-gated (K(v)),
- calcium-activated (K(Ca)),
- inward rectifier (K(ir)) and
- two-pore (K(2P)) K(+) channels.
During the last 15 years, numerous studies have demonstrated that the opening of some of these K(+) channels plays an important role in the antinociception induced by agonists of many G-protein-coupled receptors (alpha(2)-adrenoceptors, opioid, GABA(B), muscarinic M(2), adenosine A(1), serotonin 5-HT(1A) and cannabinoid receptors), as well as by other antinociceptive drugs (nonsteroidal antiinflammatory drugs [NSAIDs], tricyclic antidepressants, etc.) and natural products.
Several specific types of K(+) channels are involved in antinociception. The most widely studied are the ATP-sensitive K(+) channels (K(ATP)), members of the K(ir) family, which participate in the antinociception induced by many drugs that activate them in both the central and the peripheral nervous system.
The opening of G-protein-regulated inwardly rectifying K(+) channels (GIRK or K(ir)3), K(v)1.1 and two types of K(Ca) channels, the small- and large-conductance calcium-activated K(+) channels (SK and BK channels, respectively), also play a role in the antinociceptive effect of different drugs and natural products.
Recently, drugs that open K(+) channels by direct activation (such as openers of neuronal K(v)7 and K(ATP) channels) have been shown to produce antinociception in models of acute and chronic pain, which suggests that other neuronal K(+) channels (e.g. K(v)1.4 channels) may represent an interesting target for the development of new K(+) channel openers with antinociceptive effects
Previous studies in several different trigeminal nerve injury/inflammation models indicated that the hyperexcitability of primary afferent neurons contributes to the pain pathway underlying mechanical allodynia. Although multiple types of voltage-gated ion channels are associated with neuronal hyperexcitability, voltage-gated K+ channels (Kv) are one of the important physiological regulators of membrane potentials in excitable tissues, including nociceptive sensory neurons. Since the opening of K+ channels leads to hyperpolarization of cell membrane and a consequent decrease in cell excitability, several Kv channels have been proposed as potential target candidates for pain therapy.
In this review, we focus on common changes measured in the Kv channels of several different trigeminal neuropathic/inflammatory pain animal models, particularly the relationship between changes in Kv channels and the excitability of trigeminal ganglion (TRG) neurons. We also discuss the potential of Kv channel openers as therapeutic agents for trigeminal neuropathic/inflammatory pain, such as mechanical allodynia
Sep 11, 2012
Objective: Autoantibodies targeting voltage-gated potassium channel (VGKC) complexes cause a spectrum of neuronal hyperexcitability disorders. We investigated pain as a manifestation of VGKC-complex autoimmunity.
VGKC-complex-IgG was identified in 1,992 patients of 54,853 tested (4%). Of 316 evaluated neurologically at Mayo Clinic, 159 (50%) had pain, in isolation (28%) or with accompanying neurologic manifestations (72%), and not attributable to alternative cause. Pain was subacute in onset, chronic in course, neuropathic, nociceptive, regional, or diffuse and sometimes attributed to fibromyalgia (6%) or psychogenic cause (13%). Most patients had normal peripheral nervous system function, measured by neuropathy impairment scores and nerve conduction. Evidence of neuronal hyperexcitability (hyperhidrosis, quantitative heat-pain hyperalgesia, or electromyographic excitability) was 25-fold more common in pain patients.
Pain management required multiple medications in 70% (narcotics, 30%); 13 of 16 patients reported pain relief with immunotherapy. Pain was significantly associated with CASPR2-IgG-positivity (16% positive with pain, 7% without pain; p = 0.014) but not with LGI1-IgG. Less than 10% of 167 patients with neural autoantibodies other than VGKC-complex-IgG reported pain.
Chronic idiopathic pain is a syndromic manifestation of VGKC-complex autoimmunity. Hyperexcitability of nociceptive pathways is implicated. CASPR2-IgG significantly associates with pain, but in most patients the antigenic VGKC-complex molecule remains to be determined. VGKC-complex autoimmunity represents an important new direction for pain research and therapy.
The cause of most chronic pain disorders is unknown. Neuronal hyperexcitability conferred by DNA variants in the voltage-gated sodium channel 1.7 gene (Nav1.7) was recently identified in patients with idiopathic chronic pain with and without loss of small unmyelinated C fibers.1 An inward rectifying channel (potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2) also has been identified as an important regulator of nociceptive pain.2 Neuronal voltage-gated potassium channels (VGKC) act synergistically with these cation channels to maintain nociceptive afferent sensory neural thresholds
In this study we systematically investigated the prevalence and characteristics of pain in a large unselected cohort of patients in whom VGKC-complex-IgG was detected in serum by comprehensive evaluation for markers of neurologic autoimmunity
Our findings implicate VGKC-complex autoimmunity as a cause of chronic pain. Pain was a declared symptom in 50% of seropositive patients, 5 times more common than in control patients with other neural autoantibodies. It was typically subacute in onset, chronic in nature, descriptively nociceptive or neuropathic. In all cases comprehensive serologic testing was requested to evaluate an unexplained neurologic presentation. The pain occurred in isolation or with recognized neurologic manifestations of VGKC-complex autoimmunity,11–13 with prominent morbidity, evidenced by medication requirements (including narcotics) and referrals to pain specialists.
Documented hyperhidrosis, electromyographic hyperexcitability, and objectively measured heat-pain hyperalgesia support the concept of hyperexcitability within nociceptive pathways as a pathophysiologic basis of VGKC-complex autoimmune pain.
Although cutaneous trophic and inflammatory changes characteristic of complex regional pain disorder26 were lacking, cutaneous small fiber abnormalities (sweating and heat-pain sensation) were often the only demonstrable abnormality. As in other chronic pain disorders, symptoms were disproportionate to objectively measured neuropathic dysfunction. Affirming the inadequacy of contemporary tests for establishing the etiology of chronic pain, fibromyalgia and psychogenic pain were commonly assigned as initial diagnoses.
Most remarkably, 81% of patients receiving immunotherapy experienced pain symptom improvement not attributable to changes in standard analgesic medication or dosing, and allowing narcotics to be discontinued in some cases.
Our findings add VGKC-complex autoimmune pain to the list of potentially treatable autoimmune channelopathies.36 Identification of antigenic VGKC-complex molecules relevant to idiopathic pain represents a new direction for pain-related research, a field where fundamental causative mechanisms have been elusive.
Acute nociceptive pain is caused by the direct action of a noxious stimulus on pain-sensitive nerve endings, whereas inflammatory pain (both acute and chronic) arises from the actions of a wide range of inflammatory mediators released following tissue injury. Neuropathic pain, which is triggered by nerve damage, is often considered to be very different in its origins, and is particularly difficult to treat effectively. Here we review recent evidence showing that members of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channel family – better known for their role in the pacemaker potential of the heart – play important roles in both inflammatory and neuropathic pain. Deletion of the HCN2 isoform from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, but acute pain sensation is unaffected. This work shows that inflammatory and neuropathic pain have much in common, and suggests that selective blockers of HCN2 may have value as analgesics in the treatment of pain.
Celecoxib (CXB) is a widely prescribed COX-2 inhibitor used clinically to treat pain and inflammation.
ion channels such as the voltage-gated sodium channel, L-type calcium channel, Kv2.1, Kv1.5, Kv4.3 and HERG potassium channel were all reported to be inhibited by CXB.
Our study was aimed at establishing the role of COX-2 independent M current activation in the analgesic action of CXB
CXB, DMC and UMC are openers of Kv7/M K+ channels with effects independent of COX-2 inhibition. The analgesic effects of CXBs on pain behaviors, especially those of DMC, suggest that activation of Kv7/M K+ channels may play an important role in the analgesic action of CXB. This study strengthens the notion that Kv7/M K+ channels are a potential target for pain treatment.
- CXBs Significantly Increase the Kv7.2/7.3 Current Expressed in HEK293 Cells
- CXBs Concentration-dependently Activate Kv7.2/7.3 Channel Expressed in HEK293 Cells
- CXBs Antagonize the Nocifensive Response to Mechanical Stimuli
- CXBs Antagonize Thermal Pain Behavior
The Effects of CXBs on Neuropathic Pain in the Rat Chronic Constriction Injury Model
Growing evidence suggests that functional Kv7/M channels are expressed in peripheral sensory neurons and fibers and that their activity strongly contributes to fiber excitability
Activation of Kv7/M channels by an opener like RTG inhibits animal pain behavior while inhibition of the Kv7/M channel with a blocker like XE991 evokes spontaneous pain. Thus, it is logical to hypothesize that a drug (such as CXB) with the ability to activate Kv7/M channels is able to antagonize nociception.
Characterization of the effects of CXB analogues on Kv7/M currents lays a solid foundation for proving our hypothesis that activation of K+ currents contribute to the analgesic actions of CXB
all of these drugs were also able to antagonize both mechanical pain and thermal pain. The effectiveness of DMC in all these pain models indicates that Kv7/M current modulation by CXBs indeed contribute to the alleviation of inflammatory, mechanical and thermal pain.
In summary, our results suggest that, apart from inhibiting COX-2, activation of Kv7/M K+ currents may also contribute to the analgesic action of CXB. To our knowledge, this is the first experimental evidence that ascribes a non-COX-inhibitory mechanism to the analgesic action of a NSAID. With recent evidence that many NSAIDs can affect the functions of non-COX proteins, our results imply a need for further evaluation of NSAID effects that are independent of COX inhibition.
The use of opioid agonists acting outside the central nervous system (CNS) is a promising therapeutic strategy for pain control that avoids deleterious central side effects
We found that GIRK channels, major effectors for opioid signalling in the CNS, are absent from mouse peripheral sensory neurons but present in human and rat.
GIRK channels are indispensable for peripheral opioid analgesia,
Opioid receptors are not only localised in the brain and spinal cord, but are also expressed in peripheral sensory neurons. A promising therapeutic approach therefore has been to develop peripherally restricted opioid analgesics that target such receptors, thus avoiding centrally mediated side effects
Injection of opioid agonists at peripheral injury sites has been demonstrated to elicit analgesia in rat models of inflammatory and neuropathic pain and in human clinical investigations of postoperative and arthritic pain.
widely variable responses to opioids have been reported between rats and mice, and species differences have gained relevance for predictive validity since prototype compounds with demonstrated analgesic efficacy in rodents have often failed in humans
Here, we investigated the role of GIRK channels as mediators of peripheral opioid analgesia in primary afferent sensory neurons. We examined the expression and function of GIRK channels in mouse, rat and human peripheral sensory neurons. Strikingly, we found no evidence of such GIRK channel expression in mouse, in contrast to human and rat.
February 1, 2003
Epidural administration of local anesthetics is a widely used technique for achieving short-term regional anesthesia. A promising new approach for the management of chronic pain is the epidural administration of sustained release formulations of local anesthetics. For example, epidural injections of the local anestheticn-butyl-p-aminobenzoate (BAB) have proved to be effective in treating the intractable pain associated with advanced stages of cancer
A single epidural treatment with BAB can effectively relieve chronic pain for prolonged intervals (>30 days). Surprisingly, the pain relief produced by BAB is not associated with any demonstrable loss of motor function, suggesting that BAB selectively targets the nociceptive nerve fibers of the dorsal root
The absence of significant side effects coupled with the long-duration anesthesia provides considerable support for the use of BAB formulations in the treatment of chronic pain
Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same μ opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from μ opioid receptor. We demonstrate that the TREK-1 K(+) channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K(+) channel, acting downstream from the μ opioid receptor, might have strong analgesic effects without opioid-like adverse effects.