Protein kinase C in pain: Involvement of multiple isoforms

doi:10.1016/j.phrs.2007.04.006

Pharmacological Research

Volume 55, Issue 6, June 2007, Pages 578-589

https://doi.org/10.1016/j.phrs.2007.04.006 Get rights and content

Abstract

Pain is the primary reason that people seek medical care. At present, chronic unremitting pain is the third greatest health problem after heart disease and cancer. Chronic pain is an economic burden in lost wages, lost productivity, medical expenses, legal fees and compensation. Chronic pain is defined as a pain of greater than 2 months duration. It can be of inflammatory or neuropathic origin that can arise following nerve injury or in the absence of any apparent injury. Chronic pain is characterized by an altered pain perception that includes allodynia (a response to a normally non-noxious stimuli) and hyperalgesia (an exaggerated response to a normally noxious stimuli). This type of pain is often insensitive to the traditional analgesics or surgical intervention. The study of the cellular and molecular mechanisms that contribute to chronic pain are of the up-most importance for the development of a new generation of analgesic agents. Protein kinase C isozymes are under investigation as potential therapeutics for the treatment of chronic pain conditions. The anatomical localization of protein kinase C isozymes in both peripheral and central nervous system sites that process pain have made them the topic of basic science research for close to two decades. This review will outline the research to date on the involvement of protein kinase C in pain and analgesia. In addition, this review will try to synthesize these works to begin to develop a comprehensive mechanistic understanding of how protein kinase C may function as a master regulator of the peripheral and central sensitization that underlies many chronic pain conditions.

Section snippets

Pain

Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” It is an evolutionarily conserved sensory experience that is physiologically necessary for an organism to detect and avoid injury. The importance of this sensory system is highlighted by conditions in which pain is absent such as congenital insensitivity to pain, leprosy, or diabetic

Protein kinase C and pain

PKC is a family of serine/threonine kinases that are divided into three groups based on calcium and diacylglycerol dependence. The α, βI, βII, and γ isozymes are calcium and diacylglycerol-dependent and are termed conventional (c) PKCs. The δ, ɛ, η, and θ isozymes are calcium-independent but diacylglycerol-dependent and are termed the novel (n) PKCs. Lastly, the ξ and λ/ι isozymes are calcium and diacylglycerol-independent and termed the atypical (a) PKCs. These different PKC isozymes function

The primary afferent peripheral terminal

Following tissue damage, a variety of chemical mediators are released at the site of injury including ATP, protons, bradykinin, prostaglandins, substance P, calcitonin gene related peptide (CGRP), and proinflammatory cytokines to name just a few. These chemicals can activate and sensitize primary afferent nociceptors leading to pain that can be characterized by hyperalgesia (i.e.: warm shower water is painful on sunburned skin), and allodynia (i.e.: the touch of clothing becomes painful). These

Conclusions

In summary, this review has highlighted the importance of different PKC isozymes at different levels of the neuro-axis in both pain and analgesia such that PKCα and ɛ appear to be involved in peripheral nociception while PKCγ is important to central nociception. This does not exclude a role for other PKC isozymes in pain and analgesia but highlights the limited research on these other isozymes. This review also highlights the importance of PKC isozymes in mediating a switch from a protective

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ReviewProtein kinase C in pain: Involvement of multiple isoforms

Abstract

Section snippets

Pain

Protein kinase C and pain

The primary afferent peripheral terminal

Conclusions

Brain Res Dev Brain Res

Mol Cell Endocrinol

Neuroscience

Neurosci Lett

Neuroscience

Neuron

Neuron

Neuron

J Biol Chem

J Biol Chem

Neuropharmacology

Pain

J Biol Chem

Pain

Eur J Pharmacol

Brain Res

J Biol Chem

J Biol Chem

Pain

J Biol Chem

Life Sci

Brain Res

Neurosci Lett

Pain

J Biol Chem

Life Sci

Brain Res

Eur J Pharmacol

Trends Pharmacol Sci

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

J Biol Chem

Eur J Pharmacol

J Biol Chem

Pain

Brain Res

Pain

Brain Res

J Physiol Paris

J Biol Chem

Pain

Brain Res

Pain

Surgery in the rat during electrical analgesia induced by focal brain stimulation

Science

Endogenous pain control mechanisms: review and hypothesis

Ann Neurol

The origin of descending pathways in the dorsolateral funiculus of the spinal cord of the cat and rat: further studies on the anatomy of pain modulation

J Comp Neurol

Neurotransmitters in nociceptive modulatory circuits

Annu Rev Neurosci

Distinct cellular and regional localization of immunoreactive protein kinase C in rat brain

Proc Natl Acad Sci USA

Review
Protein kinase C in pain: Involvement of multiple isoforms