Pain Pathways Hour 2 PDF

Pain and temperatur e transmissi on Sara Jane Ward, PhD Associate Professor, Dept of Neural Sciences Spring 2025 [email protected] Session Objectives Following the required reading and today’s presentation, you should be able to: 1. Discuss the importance of physiological/nociceptive pain and...

Pain and temperatur e transmissi on Sara Jane Ward, PhD Associate Professor, Dept of Neural Sciences Spring 2025 [email protected] Session Objectives Following the required reading and today’s presentation, you should be able to: 1. Discuss the importance of physiological/nociceptive pain and contrast it from chronic/neuropathic pain 2. Identify and localize the ascending pathway that mediates pain, temperature, and crude touch 3. Understand the concept of a “pain matrix” 4. Describe the importance of the descending pain modulatory pathways 5. Describe the two mechanisms of neuropathic pain  Outline Sensory receptors and transduction Types of somatosensory receptors Mechanoreceptors Thermoreceptors, nociceptors Somatosensory pathways Dorsal column system Anterolateral System / Spinothalamic tract Pain Matrix and Descending pathway Neuropathic pain  Somatosensation Different somatosensory receptors respond to several different types of external stimuli Information about different types of stimuli travel to the brain along two different pathways 1. Touch and position pathway Mechanoreceptors 2. Pain and Temperature pathway Temperature, chemical, painful touch, painful chemical, painful temperature Types of Somatosensory Receptors: Nociceptors Pain transmission is called Receptor on sensory recepto nociception; receptors that trigger pain signals are called nociceptors Nociceptors are free nerve endings located in skin (superficial), bones, joints and blood vessels (very few nociceptors in internal organs) Mechanical, thermal or chemical damage to tissue activates receptors on free nerve endings Sensory receptor Thermoreceptors Thermal receptors are free nerve endings in the skin that respond to warmth or coolness Several receptor subtypes detect coolness to warmness across a range of temps Other subtypes of nociceptive thermoreceptors detect noxious cold and noxious heat Transduction involves ion channels on the thermoreceptor called Transient Receptor Potential (TRP) channels Opening of channels on nerve ending depolarizes or hyperpolarizes sensory neuron (Na+ or K+) Thermoreceptor  These are the receptors on the receptors! Name of receptor Type of stimulus Temperature Range TRPV2 Noxious heat Above 125 F TRPV1 Heat, capsaicin Above 109 F TRPV3 Warmth Above 88 TRPV4 (found in the Warmth; body Above 77 hypothalamus and temperature spinal cord) TRPM8 Coolness; Below 82 Menthol/Mint TRPA1 Noxious Cold Below 64 PAIN An unpleasant sensory or emotional experience Perception of pain is a product of brain’s abstraction and elaboration of sensory input, thus subjective to the individual Perception of pain varies with individuals and circumstances (genetics, past experience, current situation) Important for survival, congenital and acquired insensitivity to pain can lead to permanent damage (CITP, diabetic neuropathy, neurosyphilis) Pain reflexes can be stopped if not appropriate (step on nail near precipice, burn hands while holding a baby) In general, 2 clinical states of pain: Physiological (nociceptive) pain  the neural processes of encoding and processing noxious stimuli Neuropathic (intractable) pain  result from injury to the peripheral or central nervous system that causes permanent changes in circuit sensitivity and CNS connections.  Pathological sensitivity to temperature Like with touch, CNS injury can also lead to increased sensitivity to warm and cool Clinical example: Chemotherapy-induced peripheral neuropathy Can affect up to 75% of patients receiving certain chemotherapy regimens (esp. cisplatin and oxaliplatin) Toxicity to peripheral sensory nerves can cause paresthesia, including cold-induced paresthesia of the mouth and throat Sometimes treated with SNRIs (selective norepinephrine reuptake inhibitors) The Somatosensory Pathways Pathway Origin Termination Decussation Sensory Information (crossing) Point Transmitted Posterior Column Spinal Somatosensory Brain stem Fine touch, vibration, System cord Cortex (Medulla pressure, and (Dorsal column/ Oblongata) proprioception, medial lemniscus) Abeta, wide diameter, myelinated Anterolateral Spinal Somatosensory Spinal Cord Crude touch, pressure, System (eg. Cord Cortex Pain, temperature, Spinothalamic (Spinothalamic Adelta (20m/s) tract) tract) C fibers (2 m/s) The Somatosensory Pathways Dorsal column pathway Anterolateral pathway Anterolateral/ Spinothalamic Pathway First order sensory neurons have modified dendrite receptors in the periphery which extend to their cell bodies in the dorsal root ganglia just outside the spinal cord The whole dendrite/axon extension is either a small myelinated A fiber or an unmyelinated C fiber The axon extends from the cell body in the DRG into the dorsal horn of the spinal cord, then travel approx. two vertebral levels Anterolateral/Spinothalamic Pathway  The first order neuron then synapses with secondary neurons in the substantia gelatinosa of Rolando.  The spinothalamic tract has somatotopic organization. Its cervical, thoracic, lumbar, and sacral components are arranged from most medial to most lateral respectively  The axons decussate to the other side of the spinal cord via the anterior white commissure to the anterolateral corner of the spinal cord.  The axons of the second order neurons terminate in the ventralposteriorlateral thalamus and synapse onto third order neurons. From there, signals go to the primary somatosensory cortex, cingulate cortex, and insular cortex. Trigeminothalamic Tract  Primary axons from pain and temperature receptors for the face are part of the trigeminal nervce and have their cell bodies in the trigeminal ganglia (like DRG in anterolateral tract)  Their axons enter near the mid pons, descend as the spinal trigeminal tract through low pons, medulla and into upper cervical cord before synapsing in the spinal trigeminal nucleus, or spinal nucleus of V  In that nucleus, they synapse with second order neurons that mostly decussate and ascend in the ventral trigeminal thalamic tract to the ventral posterior medial nucleus of the  Modulation of Pain Modulation of nociceptive transmission is an adaptive process involving both excitatory and inhibitory mechanisms In the normally functioning state, the responses of 2nd order neurons can be suppressed or facilitated dependent on other events important to the organism Most of this happens below levels of consciousness.  Central pain processing: Pain matrix Pain perception is multidimensional and produced by distributed neural patterns, usually triggered by sensory inputs but modified independently of them. As the pain signal reaches the thalamus and somatosensory cortex, inputs from other brain regions modify the signal and gather information Pain experience affected by cognition, emotion, motivation, and sensation Pain matrix – brain areas that are consistently activated by, but are not exclusive to, noxious stimuli These brain regions can either enhance or reduce pain perception  Central pain processing: Pain matrix S1 informs pain intensity, modality, and location, but other brain region activities are more closely correlated to the experience of pain Anterior cingulate cortex - part of the limbic system involved in emotional learning Hyp o. Insula – self-awareness, sense of self in pain, sense of visceral pain (gastric distension) Prefrontal cortex (PFC) – anticipation of pain Activated during placebo effect with PAG Periaqueductal grey (PAG) – important site of endogenous pain inhibition Descending pathways Many areas of the pain matrix project to the PAG, a key hub of pain inhibition. The PAG projects to brain stem regions like the locus coeruleus, rostral ventromedial medulla, and raphe nucleus PAG = periaqueductal These regions send descending gray inhibitory projections to dorsal horn of spinal cord. LC = locus coeruleus RVM = rostral ventral medulla Descending pathways PAG stimulates noradrenergic, serotonergic, and opioidergic producing sites, e.g. locus coeruleus (LC), raphe nucleus, and RVM respectively Potential mechanism of SNRIs and SSRIs for treatment of neuropathic pain is to enhance inhibitory actions of the descending pain pathway, diminishing the ascending pain signals Example: Role of opioid receptors in the spinal cord Opioids can serve as a “gate” and exert analgesic effects in dorsal horn of the spinal cord (and elsewhere in the CNS) Interneurons can release neuromodulators Serotonin/Norepinephrine such as opioid peptides (endorphin, Coming from the brainstem enkephalin) Opioid receptors are inhibitory and located presynaptically on the primary sensory afferent When activated, they decrease release of glutamate and substance P Site of action of morphine and other opiate analgesics Pain signal Opioid receptor activation inhibits pain signal Substance P, Glutamate release Neuropathic pain Altered physiology of touch and pain processing caused by damage or disease to the nervous system As compared with nociceptive pain Pain persists and/or gets worse after initial damage Associated with Spontaneous pain Abnormal sensations ‘paresthesia’ Hypersensitivity pain produced by normally non-painful stimuli (allodynia) heightened pain response to a painful stimulus (hyperalgesia) Neuropathic pain Pain hypersensitivity is an adaptive response to allow healing May persist long after an injury has healed - pathological changes Two mechanisms are known to be involved: peripheral and central sensitization. Peripheral sensitization Peripheral sensitization is a reduction in threshold and an increase in responsiveness of the peripheral ends of nociceptors Occurs with injury or in certain disease states such as diabetes, in CIPN Sensitization arises due to the action of chemicals released around the site of tissue damage (histamine, bradykinin, http://xpudala.blog.163.com/blog/static/12901629220107187116783 serotonin, ATP, prostaglandins, cytokines, chemokines etc…) These chemicals can bind to receptors on the distal peripheral nerves and depolarize them closer to threshold Persistent stimulation can also lead to an increase in Na+ channel number and subtype, and TRP channels, resulting in stronger depolarization events Central sensitization Central sensitization is an increase in the excitability of neurons within the central nervous system, either due to peripheral or central nerve damage and inflammation Normal inputs begin to produce abnormal responses A burst of activity in nociceptors alters the strength of synaptic connections between the nociceptor and the neurons of the spinal cord (hyperalgesia) Low-threshold sensory fibers activated by light touch begin to activate neurons in the spinal cord that normally only respond to noxious stimuli (allodynia) Cellular and molecular mechanisms of central sensitization http://xpudala.blog.163.com/blog/static/12901629220107187116783 Three of the numerous mechanisms: 1) Alteration in glutamatergic neurotransmission/NMDA receptor hypersensitivity 2) Loss of tonic inhibitory (GABA/Glycinergic) controls (disinhibition) 3) Glial-neuronal interactions