title: Consistent sex-dependent effects of PKMζ gene ablation and pharmacological inhibition on the maintenance of referred pain.
abstract: Persistently active PKMζ has been implicated in maintaining spinal nociceptive sensitization that underlies pain hypersensitivity. However, evidence for PKMζ in the maintenance of pain hypersensitivity comes exclusively from short-term studies in males using pharmacological agents of questionable selectivity. The present study examines the contribution of PKMζ to long-lasting allodynia associated with neuropathic, inflammatory, or referred visceral and muscle pain in males and females using pharmacological inhibition or genetic ablation.
  
  
  
  Pharmacological inhibition or genetic ablation of PKMζ reduced mild formalin pain and slowly developing contralateral allodynia in nerve-injured rats, but not moderate formalin pain or ipsilateral allodynia in models of neuropathic and inflammatory pain. Pharmacological inhibition or genetic ablation of PKMζ also effectively reduced referred visceral and muscle pain in male, but not in female mice and rats.
  
  
  
  We show pharmacological inhibition and genetic ablation of PKMζ consistently attenuate long-lasting pain hypersensitivity. However, differential effects in models of referred versus inflammatory and neuropathic pain, and in males versus females, highlight the roles of afferent input-dependent masking and sex differences in the maintenance of pain hypersensitivity.
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.|Department of Anesthesia, McGill University, Montreal, QC, Canada.|Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Hibatulnaseer
authors.initials: H
authors.lastname: Nasir
authors.affiliation: Department of Physiology, McGill University, Montreal, QC, Canada.
authors.forename: Hicham
authors.initials: H
authors.lastname: Mahboubi
authors.affiliation: Division of Pharmacology & Toxicology, School of Pharmacy, University of Texas at Austin, Austin, TX, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gyawali
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ding
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: Aiste
authors.initials: A
authors.lastname: Mickeviciute
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.|Department of Anesthesia, McGill University, Montreal, QC, Canada.
authors.forename: J Vaigunda
authors.initials: JV
authors.lastname: Ragavendran
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.|Department of Anesthesia, McGill University, Montreal, QC, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Laferrière
authors.affiliation: Department of Physiology, McGill University, Montreal, QC, Canada.
authors.forename: Ursula
authors.initials: U
authors.lastname: Stochaj
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada terence.coderre@mcgill.ca.|Department of Anesthesia, McGill University, Montreal, QC, Canada.|Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Coderre
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000633:toxicity; D057846:Cell-Penetrating Peptides; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D055666:Lipopeptides / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D012727:Sex Characteristics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000099221:Protein Kinase C zeta
chemical_list: D002211:Capsaicin; D057846:Cell-Penetrating Peptides; D005620:Freund's Adjuvant; D055666:Lipopeptides; D010880:Piperidines; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C568285:zeta-inhibitory peptide; C069701:NPC 15437
keywords: PKC/Mζ knock-out; Sex differences; analgesia; antinociception; central sensitization; muscle pain; protein kinase M-zeta; tactile allodynia; visceral pain