calpain and Pain

Exercise-induced muscle damage is a well documented phenomenon that often follows unaccustomed and sustained metabolically demanding activities. This is a well researched, but poorly understood area, including the actual mechanisms involved in the muscle damage and repair cycle. An integrated model of muscle damage has been proposed by Armstrong and is generally accepted. A more recent aspect of exercise-induced muscle damage to be investigated is the potential of estrogen to have a protective effect against skeletal muscle damage. Estrogen has been demonstrated to have a potent antioxidant capacity that plays a protective role in cardiac muscle, but whether this antioxidant capacity has the ability to protect skeletal muscle is not fully understood. In both human and rat studies, females have been shown to have lower creatine kinase (CK) activity following both eccentric and sustained exercise compared with males. As CK is often used as an indirect marker of muscle damage, it has been suggested that female muscle may sustain less damage. However, these findings may be more indicative of the membrane stabilising effect of estrogen as some studies have shown no histological differences in male and female muscle following a damaging protocol. More recently, investigations into the potential effect of estrogen on muscle damage have explored the possible role that estrogen may play in the inflammatory response following muscle damage. In light of these studies, it may be suggested that if estrogen inhibits the vital inflammatory response process associated with the muscle damage and repair cycle, it has a negative role in restoring normal muscle function after muscle damage has occurred. This review is presented in two sections: firstly, the processes involved in the muscle damage and repair cycle are reviewed; and secondly, the possible effects that estrogen has upon these processes and muscle damage in general is discussed. The muscle damage and repair cycle is presented within a model, with particular emphasis on areas that are important to understanding the potential effect that estrogen has upon these processes.

Topics: Calcium; Calpain; Creatine Kinase; Cytokines; Estrogens; Exercise; Homeostasis; Humans; Muscle, Skeletal; Myositis; Pain; Perception

Topics: Anemia, Sickle Cell; Animals; Calpain; Disease Models, Animal; Gene Deletion; Gene Silencing; Humans; Mice; Mice, Knockout; Pain

Loss of synaptic inhibition by γ-aminobutyric acid and glycine due to potassium chloride cotransporter-2 (KCC2) down-regulation in the spinal cord is a critical mechanism of synaptic plasticity in neuropathic pain. Here we present novel evidence that peripheral nerve injury diminishes glycine-mediated inhibition and induces a depolarizing shift in the reversal potential of glycine-mediated currents (E(glycine)) in spinal dorsal horn neurons. Blocking glutamate N-methyl-D-aspartate (NMDA) receptors normalizes synaptic inhibition, E(glycine), and KCC2 by nerve injury. Strikingly, nerve injury increases calcium-dependent calpain activity in the spinal cord that in turn causes KCC2 cleavage at the C terminus. Inhibiting calpain blocks KCC2 cleavage induced by nerve injury and NMDA, thereby normalizing E(glycine). Furthermore, calpain inhibition or silencing of μ-calpain at the spinal level reduces neuropathic pain. Thus, nerve injury promotes proteolytic cleavage of KCC2 through NMDA receptor-calpain activation, resulting in disruption of chloride homeostasis and diminished synaptic inhibition in the spinal cord. Targeting calpain may represent a new strategy for restoring KCC2 levels and tonic synaptic inhibition and for treating chronic neuropathic pain.

Topics: Animals; Biological Transport; Calpain; Chlorides; Electrophysiology; Glutamic Acid; Homeostasis; K Cl- Cotransporters; Male; Neuralgia; Neuronal Plasticity; Pain; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA, Small Interfering; Symporters; Synapses

The purpose of this study was to compare the responsiveness of changes in Ca(2+)-content and calpain-calpastatin gene expression to concentric and eccentric single-bout and repeated exercise. An exercise group (n = 14) performed two bouts of bench-stepping exercise with 8 weeks between exercise bouts, and was compared to a control-group (n = 6). Muscle strength and soreness and plasma creatine kinase and myoglobin were measured before and during 7 days following exercise bouts. Muscle biopsies were collected from m. vastus lateralis of both legs prior to and at 3, 24 h and 7 days after exercise and quantified for muscle Ca(2+)-content and mRNA levels for calpain isoforms and calpastatin. Exercise reduced muscle strength and increased muscle soreness predominantly in the eccentric leg (P < 0.05). These responses as well as plasma levels of creatine kinase and myoglobin were all attenuated after the repeated eccentric exercise bout (P < 0.05). Total muscle Ca(2+)-content did not differ between interventions. mRNA levels for calpain 2 and calpastatin were upregulated exclusively by eccentric exercise 24 h post-exercise (P < 0.05), with no alteration in expression between bouts. Calpain 1 and calpain 3 mRNA did not change at any specific time point post-exercise for either intervention. Our mRNA results suggest a regulation on the calpain-calpastatin expression response to muscle damaging eccentric exercise, but not concentric exercise. Although a repeated bout effect was demonstrated in terms of muscle function, no immediate support was provided to suggest that regulation of expression of specific system components is involved in the repeated bout adaptation.

Topics: Adaptation, Physiological; Adult; Calcium; Calcium-Binding Proteins; Calpain; Creatine Kinase; Exercise; Humans; Male; Muscle Contraction; Muscle Proteins; Muscle Strength; Myoglobin; Pain; Pain Measurement; Quadriceps Muscle; RNA, Messenger; Time Factors; Up-Regulation

Several molecules and cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase implicated in the development and disease of the mammalian nervous system. The precise role of this kinase in sensory pathways has not been well characterized. Here we report a molecular role for Cdk5 in nociception. We identified the expression of Cdk5 and its activator p35 in nociceptive neurons, which is modulated during a peripheral inflammatory response. Increased calpain activity in sensory neurons after inflammation resulted in the cleavage of p35 to p25, which forms a more stable complex with Cdk5 and, consequently, leads to elevation of Cdk5 activity. p35 knockout mice (p35(-/-)), which exhibit significantly decreased Cdk5 activity, showed delayed responses to painful thermal stimulation compared with WT controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, were more sensitive to painful thermal stimuli than were controls. In conclusion, our data demonstrate a role for Cdk5/p35 activity in primary afferent nociceptive signaling, suggesting that Cdk5/p35 may be a target for the development of analgesic drugs.

Topics: Animals; Calpain; Cells, Cultured; Cyclin-Dependent Kinase 5; Female; Ganglia, Spinal; Hot Temperature; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nerve Fibers; Nociceptors; Pain; Phosphotransferases; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord; Trigeminal Ganglion