Pain
-
Injuries can induce adaptations in pain processing that result in amplification of signaling. One mechanism may be analogous to long-term potentiation and involve the atypical protein kinase C, PKMζ. The possible contribution of PKMζ-dependent and independent amplification mechanisms to experimental neuropathic pain was explored in rats with spinal nerve ligation (SNL) injury. ⋯ Thus, PKMζ-dependent amplification contributes to nerve injury-induced aversiveness within the rACC. Moreover, unlike mechanisms maintaining memory, the consequences of PKMζ inhibition within the rACC are not permanent in neuropathic pain, possibly reflecting the re-establishment of amplification mechanisms by ongoing activity of injured nerves. In the spinal cord, however, both PKMζ-dependent and independent mechanisms contribute to amplification of evoked responses, but apparently not spontaneous pain.
-
Chronic low back pain (LBP) is a complex, multifactorial disorder with unclear underlying mechanisms. In humans and rodents, decreased expression of secreted protein acidic rich in cysteine (SPARC) is associated with intervertebral disc (IVD) degeneration and signs of LBP. The current study investigates the hypothesis that IVD degeneration is a risk factor for chronic LBP. ⋯ Morphine (6 mg/kg, i.p.) reduced cutaneous sensitivity and alleviated axial discomfort in SPARC-null mice. Ageing SPARC-null mice mirror many aspects of the complex and challenging nature of LBP in humans and incorporate both anatomic and functional components of the disease. The current study supports the hypothesis that IVD degeneration is a risk factor for chronic LBP.
-
Accumulated evidence suggests that the C-C motif chemokine ligand 5 (CCL5) modulates migration of inflammatory cells in several pathological conditions. This study tested the hypothesis that lack of CCL5 would modulate the recruitment of inflammatory cells to painful, inflamed sites and could attenuate pain in a murine chronic neuropathic pain model. Nociceptive sensitization, immune cell infiltration, multiple cytokine expression, and opioid peptide expression in damaged nerves were studied in wild-type (CCL5 +/+) and CCL5-deficient (CCL5 -/-) mice after partial sciatic nerve ligation (PSNL). ⋯ We demonstrated that lack of CCL5 modulated cell infiltration and the proinflammatory milieu within the injured nerve. Attenuated behavioral hypersensitivity in CCL5 -/- mice observed in the current study could be a result of decreased macrophage infiltration, mobilization, and functional ability at injured sites. Collectively, the present study results suggest that CCL5 receptor antagonists may ultimately provide a novel class of analgesics for therapeutic intervention in chronic neuropathic pain.
-
Damage to peripheral nerves causes significant remodeling of peripheral innervation and can lead to neuropathic pain. Most nociceptive primary afferents are unmyelinated (C fibers) and subdivided into peptidergic and nonpeptidergic fibers. Previous studies have found nerve injury in the trigeminal system to induce changes in small-diameter primary afferent innervation and cause significant autonomic sprouting into the upper dermis of the lower-lip skin of the rat. ⋯ These changes were associated with significant increase in glial-derived nerve growth factor levels in the lower-lip skin. While IB4-saporin treatment had no effect on evoked mechanical thresholds when von Frey hairs were applied to the lower-lip skin, ablation of nonpeptidergic fibers in a chronic constriction injury model caused significant sympathetic and parasympathetic fiber sprouting, and led to an exacerbated pain response. This was an unexpected finding, as it has been suggested that nonpeptidergic fibers play a major role in mechanical pain, and suggests that these fibers play a complex role in the development of neuropathic pain.
-
Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. ⋯ In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages.