My laboratory is interested in understanding and developing new treatments for chronic 'neuropathic' pain. Acute tissue injury produces 'nociceptive' pain. Because it promotes avoidance of tissue damage, this unpleasant, yet vital physiological response ensures an individual's survival . By contrast, 'neuropathic' pain induced by injury to, or disease of, the nervous system is a major health problem. Because it persists for months or years after any injury has healed, neuropathic pain serves no obvious biological purpose. It is associated with diabetic, postherpetic and HIV-related neuropathies, as well as with traumatic nerve, brain or spinal cord injury. The prevalence of neuropathic pain has been estimated at 1.5% within the general population. This would mean about 100,000,000 people worldwide! Standard pharmacological interventions include opioids, ketamine, amitryptyline, gabapentin, pregabalin or other anticonvulsants. All too frequently however, these drugs display limited effectiveness or dose-limiting side effects that range from sedation and dizziness to psychosis and hallucinations.
In my laboratory, we try to meet the urgent need for new therapies by understanding the long-term electrophysiological changes that occur in sensory and spinal nerves when they are damaged. This involves altered responsiveness to analgesic and other drugs as well as alterations in ion channel properties and neurotransmitter actions. Experiments are done using whole-cell patch clamp recordings from the cell bodies of sensory nerves in rat dorsal root ganglia as well as `slice-patch' recordings from the dorsal horn of the spinal cord. The latter are complimented using confocal Ca2+ imaging experiments in collaboration with Dr. Klaus Ballanyi (Department of Physiology) and behavioural and biochemical studies in collaboration with Drs. Bradley Kerr (Anesthesiology and Pain Medicine) and Elena Posse de Chaves (Pharmacology).
We have recently developed an organotypic culture system of spinal cord which allows us to put "pain in a dish" and explore its molecular and cellular mechanisms. We also consider the involvement of non-neuronal cells such as microglia and astrocytes in the development of chronic pain. Current projects involve 1) exploring the role of brain derived neurotrophic factor in the onset of chronic neuropathic pain 2) elucidating the mechanism of action of gabapentin, one of the first line drugs in the treatment of neuropathic pain 3) exploring the role of inflammatory mediators such as the interleukins in the development of chronic pain 4) in collaboration with Dr. Christopher Power (Neurology) exploring the role of viral proteins in the development of AIDs related pain.
Alles SR, Bandet MV, Eppler K, Noh MC, Winship IR, Baker G, Ballanyi K and Smith PA. (2017) Acute Anti-Allodynic Action of Gabapentin in Dorsal Horn and Primary Somatosensory Cortex: Correlation of Behavioural and Physiological Data. Neuropharmacology 113(Pt A):576-590. PMID: 27856391.
Alles SR and Smith PA. (2016) The Anti-Allodynic Gabapentinoids: Myths, Paradoxes, and Acute Effects. Neuroscientist [Epub ahead of print]. PMID: 27118808.
Stebbing MJ, Balasubramanyan S and Smith PA. (2016) Calbindin-D-28K like immunoreactivity in superficial dorsal horn neurons and effects of sciatic chronic constriction injury. Neuroscience 324:330-43. PMID: 26975894.
Chen Y, Derkach VA and Smith PA. (2016) Loss of Ca2+-Permeable AMPA Receptors in Synapses of Tonic Firing Substantia gelatinosa Neurons in the Chronic Constriction Injury Model of Neuropathic Pain. Exp Neurol 279:168-77. PMID: 26948545.
Stemkowski PL, Noh M, Chen Y and Smith PA. (2015) Increased Excitability of Medium-Sized Dorsal Root Ganglion Neurons by Prolonged Interleukin-1β Exposure is K+ Channel Dependent and Reversible. J of Physiol 593(16):3739-55. PMID: 26110238.
Haile Y, Nakhaei-Nejad M, Boakye PA, Baker G, Smith PA, Murray AG, Giuliani F and Jahroudi N. (2015) Reprogramming of HUVECs into induced pluripotent stem cells (HiPSCs), generation and characterization of HiPSC-derived neurons and astrocytes. PLoS One 10(3):e0119617. PMID: 25789622.
Biggs JE, Boakye PA, Ganesan N, Stemkowski PL, Lantero A, Ballanyi K and Smith PA. (2014) Analysis of the Long-Term Actions of Gabapentin and Pregabalin in Dorsal Root Ganglia and Substantia Gelatinosa. J Neurophysiol. 112(10):2398-2412. PMID: 25122705.
Biggs JE, Stemkowski PL, Knaus EE, Chowdhury MA, Ballanyi K and Smith PA. (2015) Suppression of Network Activity in Dorsal Horn by Gabapentin Permeation of TRPV1 Channels; Implications for Drug Targeting in Specific Neuronal Populations. Neurosci Letts. 584 397-402. PMID: 25079903.
Smith PA. (2014) BDNF: No gain without pain? Neuroscience. 283 107-123. PMID: 24887639.
Noh S, Kumar N, Bukhanova N, Chen Y, Stemkowsi PL and Smith PA. (2014) The heart-rate-reducing agent, ivabradine, reduces mechanical allodynia in a rodent model of neuropathic pain. Eur J Pain 18(8):1139-47. PMID: 24677354.
Stemkowski PL, Biggs JE, Chen Y, Bukhanova N, Kumar N and Smith PA (2013) Understanding and Treating Neuropathic Pain Neurophysiology 45:75-86.
Smith PA. (2013) Synapses Share the Pain: New Insight into the Neurophysiology of Secondary Hyperalgesia. Pain 154(8):1482-3. PMID: 23707293.
Stemkowski PL and Smith PA (2013) An overview of animal models of neuropathic pain pp 33-50 in Neuropathic Pain, Causes, Management and Understanding ed C., Toth and D. Molin, Cambridge University Press, Cambridge UK
Clanachan AS and Smith PA (2012) Preface: special issue commemorating the 50th anniversary of the Department of Pharmacology at the University of Alberta. Can J Physiol Pharmacol 90(6):iii. PMID: 22616649.
Biggs JE, Lu VB, Kim HJ, Lai A, Todd KG, Ballanyi K, Colmers WF and Smith PA (2012) Defined Medium Organotypic Cultures of Spinal Cord Put ‘Pain in a Dish’. Isolated Central Nervous System Circuits Neuromethods (Humana Press) Vol 73:405-436
Lu VB, Smith PA and Rashiq S (2012) The excitability of dorsal horn neurons is affected by cerebrospinal fluid from humans with osteoarthritis. Can J Physiol Pharmacol. 90(6):783-790. PMID: 22506885.
Stemkowski PL and Smith PA (2012) Long-term IL-1beta exposure causes subpopulation-dependent alterations in rat dorsal root ganglion neuron excitability. J Neurophysiol. 107(6):1586-1597. PMID: 22170966.
Stemkowski PL and Smith PA. (2012) Sensory neurons, ion channels, inflammation and the onset of neuropathic pain. Can J Neurol Sci. 39(4):416-435. PMID: 22728849.
Lu VB, Colmers WF and Smith PA (2012) Long-term actions of BDNF on inhibitory synaptic transmission in identified neurons of the rat substantia gelatinosa. J Neurophysiol 108(2):441-452. PMID: 22496528.